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THE 
INTERNAL  SECRETIONS 


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THE 
INTERNAL  SECRETIONS 

THEIR  PHYSIOLOGY  AND  APPLICATION  TO 
PATHOLOGY 

BY 

E.  GLEY,  M.  D. 

Member  of  the  Academy  of  Medicine  of  Paris;  Professor  of 
Physiology  in  the  College  of  France,  etc. 

TRANSLATED  FROM  THE  FRENCH  AND  EDITED  BY 

MAURICE  FISHBERG,  M.  D. 

Clinical  Professor  of  Medicine,  New  York  University  and  Bellevue  Hospital 

Medical  College;  Attending  Physician,  Montefiore  Home  and 

Hospital  for  Chronic  Diseases 

AUTHORIZED  TRANSLATION 


NEW  YORK 

PAUL  B.  HOEBER 
1917 


Copyright,  1917, 
By  PAUL  B.  HOEBER 


Published  April,  1917 


Printed  in  the  United  States  of  America. 


PREFACE 

Professor  Gley's  book,  of  which  a  trans- 
lation is  here  offered,  is  believed  to  fill  a 
gap  in  onr  literature  on  the  physiology  and 
pathology  of  the  endocrine  glands.  It  ap- 
pears that  the  few  available  books  on  the 
subject  are,  in  many  cases,  too  extensive 
for  the  busy  practitioner  who  wants  to  in- 
form himself  about  the  present  status  of 
the  theory  of  internal  secretion  and  its  ap- 
plication in  every-day  practice.  Many, 
also,  it  would  seem  to  the  unbiased  critic, 
err  by  having  too  optimistic  a  viewpoint, 
especially  when  discussing  organotherapy. 
Professor  Gley's  study  treats  the  subject 
in  a  thoroughly  scientific,  critical,  yet  not 
ultra-conservative,  spirit,  pointing  out  not 
only  what  we  actually  know  in  this  very 
promising  field,  but  also  being  careful  to 

5 


6  PEEFACE 

indicate  what  we  do  not  know  and  suggest- 
ing the  proper  methods  to  be  pursued  if  we 
are  to  learn  enough  of  the  subject  to  make 
these  glands,  and  their  products,  available 
in  rational  therapeutics.  For  these  reasons 
Gley's  book  is  given  to  those  who  are  not 
prepared  to  read  it  in  the  original  French. 

The  translation  has  been  made  quite 
freely;  no  literal  rendering  of  the  French 
text  has  been  attempted.  Great  care  has, 
however,  been  taken  to  express  the  spirit  of 
the  author  in  clear  and  simple  English.  No 
additions  of  any  consequence  have  been 
made  because  it  was  deemed  best  to  leave 
the  text  as  originally  presented  by  the 
author.  Several  additional  paragraphs 
sent  in  by  Professor  Grley,  especially  for 
this  edition,  have  been  incorporated  with  a 
view  to  bringing  the  work  up  to  date,  and 
to  elucidate  some  points  which  needed  am- 
plification.   Also,  an  index  has  been  added. 

M.  F. 

New  York, 
April,  1917. 


CONTENTS 


PAGE 

Preface    5 

Introduction:    The   Differences    between    the 

Two  Kinds  of  Secretions   ....      11 

CHAPTER 

I.     The  Concept  of  Internal  Secretions;  Its 

Origin  and  Development  ....  15 

I.     The  Precursors  of  the  Doctrine        .  16 

II.     The  Founders  of   the   Doctrine         .  32 
III.     The  Present  Conception  of  Internal 

Secretion 59 

II.     Distinctive  Characteristics  of  the  Inter- 
nal Secretory  Glands  and  the  Princi- 
pal Products  of  Their  Activities     .        .  77 
I.     Conditions  Essential  to  Internal  Secretion  77 

1.  Histological  Conditions       ...  82 

2.  Chemical  Conditions    ....  89 

3.  Physiological  Conditions     ...  92 
Action  of  Organic  Extracts         .         .  105 

Theoretical  Objections     .         .         .113 
Objections  of  Fact  ....     115 
II.    Principal  Distinctive  Characteristics 
of   the   Products    of    Internal   Se- 
cretion   134 

Nutritive  Substances  ....     134 
7 


8  CONTENTS 

CHAPTEB  PAGE 

Morphogenetic    Substances    (Harmo- 

zones) 134 

The  Hormones 143 

The  Parhormones       ....     146 
The  Distinctive  Characteristics  of  the 
Endocrine  Products         .         .         .     156 
III.    Classification  of  the  Internal  Secre- 
tory Glands  and  the  Products  Which 
They  Secrete 167 

III.    The  Function  of  the  Internal  Secretory 

Glands 177 

I.     The  Normal  Activities      .         .         .         .177 
The  Eeciprocal  Glandular  Actions  or 

Humoral  Correlations     .         .         .  182 
Eeciprocal    Relations     between    the 

Pancreas  and  Adrenals  .         .        .  194 
Eeciprocal    Relations    between    the 

Thyroid  and  Adrenals    .         .         .  201 
Eeciprocal    Relations    between    the 

Thyroid  and  Pancreas    .         .         .  208 
Reciprocal    Relations     between     the 

Thyroid  and  the  Gonads        .         .  210 
II.     The  Diseased  Function      .         .        .        .213 

Hypersecretion 214 

Hyposecretion 219 

Trophic  Deviations    ....  225 

Index 235 


INTEODUCTION 

THE   DIFFERENCES   BETWEEN   THE   TWO   KINDS 
OF   SECRETIONS 


INTRODUCTION 

THE   DIFFERENCES   BETWEEN    THE   TWO    KINDS 
OF   SECRETIONS 

The  subject  of  secretions  has  always 
formed  one  of  the  most  important  chap- 
ters in  physiology.  The  glands  which 
manufacture  the  digestive  ferments,  and 
those  which  serve  to  eliminate  the  waste 
products  of  nutrition,  are  essential  to  the 
organism.  It  may  be  stated  that  there  is 
not  a  single  secretion  whose  role  does  not 
appear  to  be  at  least  very  useful,  if  not 
absolutely  necessary,  to  the  integrity  of 
the  vital  functions.  The  recognition  of  the 
vast  importance  of  the  glandular  organs 
and  their  products  has  been  practically 
universal  for  the  past  twenty-five  years. 

Only  within  this  period,  as  a  result  of  the 
11 


12  INTRODUCTION 

inspiration  of  Brown-Sequard's  fundamen- 
tal work  published  in  1890,  have  physiolo- 
gists undertaken  the  study  of  the  glands 
having  an  internal,  or  endocrine,  secretion ; 
i.e.,  glands  distributing  the  products  of 
their  activities,  not  through  the  cutaneous 
surface  or  gastro-intestinal  mucous  mem- 
brane and  out  of  the  body,  but  directly  to 
the  tissues,  through  the  agency  of  the 
blood  stream. 


THE    CONCEPT    OF    INTERNAL    SECRETION;    ITS 
ORIGIN   AND   DEVELOPMENT 


THE    CONCEPT    OF    INTERNAL    SECRETION;    ITS 
ORIGIN  AND  DEVELOPMENT 

"Nothing  about  a  science  is  more  interest- 
ing than  the  progress  of  that  science  itself." 
—  (Laennec.) 

Complete  knowledge  of  a  physiological 

problem,  like  that  of  a  living  being,  can  be 

acquired  only  by  grasping  the  problem  at 

its  very  origin  and  following  it  through  all 

its  successive  phases  of  development.    In 

order  to  connect  physiological  facts,  which 

are  usually  so  complex,  with  one  another, 

to   coordinate  and  systematize  the  ideas 

which  may  be  engendered  by  the  facts,  it 

is  essential  to  distinguish  the  evolution  of 

theory  from  accumulated  data.     In  other 

words,  nothing  is  more  useful  in  studies 
15 


16    THE  INTEENAL  SECBETIONS 

of  this  sort  than  a  good  historical  review 
of  the  subject. 

To  the  doctrine  of  internal  secretions  are 
inseparably  attached  the  names  of  Claude 
Bernard  and  Brown-Sequard;  the  one  the 
initiator,  the  other  the  resurrector  of  the 
doctrine,  as  I  was  the  first  to  show.1 

I.      THE   PRECURSORS   OF   THE   DOCTRINE 

But  Claude  Bernard  and  Brown-Sequard 
had  their  precursors;  in  fact,  they  are 
found  in  medical  literature. 

1.   In  1897,2  I  called  attention  to  a  work 

1 "  Conception  et  classification  physiologiques  des 
glandes"  (Revue  scientifique,  1893,  MI,  8-17) ;  "ExposS 
des  donnees  experimentales  sur  les  correlations  fonc- 
tionnelles  chez  les  animaux,,  (L'Anne'e  biologique,  1897, 
I,  313-330). 

2 In  my  article  in  L' Annie  biologique  quoted  above. 
It  is  not  without  interest  to  know  that  Claude  Bernard 
had  read  Legallois  (a  French  physician  and  physiologist, 
celebrated  for  his  investigations  of  the  action  of  the 
heart  and  the  nervous  system;  died  in  1810).  "It  has 
been  recognized  for  a  long  time,"  says  Bernard, 
("Lecons  sur  les  .  .  .  liquides  de  l'organisme,"  1859, 
I,  p.  321),  "that  although  it  were  possible  to  admit  the 


CONCEPT  OF  SECEETION       17 

of  Legallois,  hitherto  apparently  forgotten, 
in  which  it  is  seen  that,  more  than  a  cen- 
tury ago,  this  physiologist  had  clear  no- 
tions of  the  connection  which  must  exist 
between  the  various  secretions,  and  the 
complexity  of  the  composition  of  the  ve- 
nous blood.  The  text  runs  thus :  ' '  Consid- 
ering the  homogeneity  of  the  arterial  blood 
and  the  heterogeneity  of  the  venous  blood 
we  may  conclude  that  ...  it  would  be  a 
supreme  triumph  of  the  chemistry  of  the 
living  body  to  find  connections  between  the 
arterial  blood,  the  substances  so  secreted  in 
each  organ  and  the  corresponding  venous 
blood,  in  the  normal  as  well  as  in  the  patho- 
logical states  of  various  animals;  to  find 
differences  between  the  various  kinds  of 
venous  blood ;  finally  to  discover  that  these 

homogeneity  of  the  arterial  blood,  the  venous  blood  can- 
not be  regarded  as  having  the  same  composition  through- 
out its  course.  Legallois,  examining  this  question  in  a 
purely  speculative  work,  had  already  concluded  that  the 
arterial  blood  is  everywhere  identical  in  composition,  but 
declared  that  the  venous  blood  was  not  so  constant," 


18     THE  1NTEENAL  SECEETIONS 

differences  vary  as  do  the  corresponding 
secretions. 

"Once  arrived  at  this  degree  of  perfec- 
tion, it  would  often  be  possible  to  solve  for 
the  unknown  in  the  equation:  arterial 
blood  =  a  secretion  +  the  corresponding 
venous  blood; 3  that  is,  given  the  left  hand 
member  of  the  equation,  and  the  composi- 
tion of  the  corresponding  venous  blood, 
chemical  science  could  almost  determine 
what  would  be  the  character  of  the  secre- 
tion. " 4  However  keen  it  may  have  been 
for  a  physiologist  of  that  time  (1801)  to 
recognize  intuitively  an  essential  part  of 
the  problem  of  the  mechanism  of  secretion, 
it  must  nevertheless  be  noted  that  the  ideas 
of  Legallois  are  not  specific  and  that  they 
apply  to  all  glands,  not  differentiating 
those  which  have  since  been  designated  as 

*  These  words  were  underscored  by  Legallois. 

4  Legallois,  ' '  Le  sang,  est-il  identique  dans  tous  les 
vaisseaux  qu'il  parcourt?"  Inaugural  dissertation 
given  before  the  School  of  Medicine  in  Paris,  Sept., 
1801  ("CEuvres  de  Legallois,"  II,  209-10). 


CONCEPT  OF  SECEETION       19 

glands  of  internal  secretion.  The  impor- 
tance of  this  last  reservation  in  the  study 
of  the  origin  of  the  theory  of  the  endocrine 
glands  is  evident. 

2.  Following  a  suggestion  of  Max  Neu- 
berger,5  Biedl  wishes  to  attribute  a  similar 
conception  to  another  French  physician, 
Theophile  Bordeu,  who  lived  even  before 
Legallois.  Biedl  says:  "In  his  treatise 
on  'L 'Analyse  medicinale  du  sang,'  which 
appeared  in  1775,  Bordeu  expresses  the 
opinion  that  each  organ  serves  as  a  center 
for  the  preparation  of  a  specific  substance 
which  is  discharged  into  the  blood,  and 
that  these  substances  are  useful  to  the  or- 
ganism and  necessary  for  its  integrity. 
The  specific  substances  coming  from  their 
particular  organs  perhaps  reach  the  blood 
through  the  medium  of  the  lymphatics.  It 
seemed  to  him  to  have  been  conclusively 
demonstrated   that   the   venous   blood   of 

5  Max  Neuberger,  Theophile  Bordeu  als  Vorlauf er 
der  Lehre  der  Inneren  Sekretion"  (Wiener  Iclinische 
Woch.,  Sept.  28,  1911,  XXIV,  1367). 


20     THE  INTERNAL  SECRETIONS 

various  regions  presents  important  quali- 
tative differences."  6  Asa  matter  of  fact, 
Bordeu  did  not  express  himself  so  clearly. 
The  "Analyse  medicinale  du  sang,"  which 
Biedl  quotes,  is  a  booklet  whose  title  is 
rather  too  ambitious.  I  shall  quote  sev- 
eral typical  passages  from  which  it  will 
be  clear  that  the  author's  thoughts  were 
very  vague.  After  a  series  of  truisms  on 
the  characteristics  of  each  part  of  the  liv- 
ing body,  the  author  concludes :  "I  believe 
it  to  be  certain  that  every  organ  keeps  its 
own  particular  place,  as  I  have  just  said, 
and  that  it  lives  its  own  independent  life 
.  .  .  and  always  diffuses  around  itself,  in 
its  atmosphere  and  province,  exhalations 
and  odors;  emanations  which  have  taken 
on  its  manners  and  its  ways,  which  are,  in 
short,  true  parts  of  the  organ  itself. 

"I   do  not   regard  these   emissions   as 
entirely    useless    and    therefore    only    of 

6  A.  Biedl,  "Innere  Sekretion,"  2nd  Ed.,  Berlin  and 
Vienna,  1913,  I,  p.  5. 


CONCEPT  OF  SECRETION       21 

mechanical  utility;  I  think  they  are  use- 
ful and  necessary  for  the  existence  of 
the  entire  organism.  The  seminal  fluid 
imparts,  as  is  well  known,  a  manly  and 
firm  bearing  to  all  parts  of  the  body, 
since  it  is  in  a  position  to  be  pumped  into 
and  come  back  from  the  mass  of  humors 
and  solids,  by  the  work  of  its  natural  or- 
gans ;  it  confirms  anew  the  living  nature  of 
the  individual,  partly  subjected  to  the  ac- 
tion of  this  fertile  fluid.  .  .  .  Examine  the 
blood  that  returns  from  each  of  the  princi- 
pal regions  of  the  body,  that  from  the  head, 
from  the  breast  and  from  the  abdomen;  it 
is  evident 7  that  the  blood  from  each  of 
these  regions  has  particular  qualities  that 
it  has  acquired  in  the  tissues  of  the  parts 
from  which  it  returns.  Finally,  I  accept  as 
a  fact,  which  has  been  medically  verified, 
the  assertion  that  each  organ  is  continu- 
ously diffusing  emanations  into  the  blood ; 

7  It  is  useless  to  add  that  these  words  were  uttered 
without  observation  and  a  fortiori  of  all  analysis. 


22     THE  INTERNAL  SECRETIONS 

and  if  it  were  possible  to  base  a  deduction 
on  some  part  of  the  anatomists'  discovery 
of  venous  lymphatics,  I  would  say  that  this 
gelatinous  liquid  has  particular  vessels  so 
that  it  may  be  more  surely  brought  back 
into  the  blood-stream  with  the  individual 
qualities  that  it  has  acquired  in  the  inter- 
nal tissues  of  each  organ,  in  order  to  instil 
into  the  chyle,  into  the  thoracic  visceral 
tract,  the  properties  and  characteristics  pe- 
culiar to  the  parts  of  which  it  is  composed. 
Some  one  has  found  lymphatic  veins  in 
the  testicles  and  has  ascribed  to  them  the 
function  of  returning  the  seminal  fluid  into 
the  blood.  It  was  not  necessary  to  know  of 
the  existence  of  these  veins  to  realize  the 
fact  that  absorption  of  the  seminal  fluid 
takes  place."  8 

We  can  easily  see  from  the  above  how 
much  clearer  were  the  ideas  of  Legallois. 
But  once  on  a  pathological  basis — and  this 

8  Theophile  Bordeu,  ' '  GEuvres  completes, ' '  edition 
Kicherand,  vol.  II,  pp.  942-943,  Paris,  1818. 


CONCEPT  OF  SECRETION       23 

has  not  escaped  Neuberger  or  Biedl9 — 
Bordeu's  progress  appears  to  be  a  little 
more  certain.  "The  flowing  back  of  the 
bile,"  he  says, "for  example,  its  elaboration 
in  the  blood,  its  diffusion  through  all  the 
tissues  of  the  body,  the  color  that  it  gives 
to  solids  and  to  liquids,  are  well  known 
phenomena.  We  may  indubitably  conclude 
from  this  .  .  .  that  throughout  life,  and 
even  when  in  the  best  of  health,  a  constant 
interchange  is  going  on  between  the  liver 
and  all  the  humors  and  solids  of  the  body. 
The  superabundance  of  humors  present  in 
some  of  the  diseases  to  which  their  organs 
are  subject,  is  proof  of  the  existence  of 
passages  by  which  the  humors  pass  when 
the  organism  is  in  a  normal  condition.  .  .  . 
The  diversity  of  temperaments  was  for- 
merly,   not    without    some    semblance    of 

9 ' '  That  Bordeu  has  presented  the  pathological  sig- 
nificance of  anomalies  of  excretion,  is  shown  by  his  re- 
mark: 'Physicians  should  follow  and  classify  the  vari- 
ous refluxes  which  take  place  through  the  fault  of  each 
organ  in  particular  '  "  (A.  Biedl,  loc.  cit.,  p.  5). 


24     THE  INTERNAL  SECRETIONS 

truth,  attributed  to  an  oversupply  of  hu- 
mors. I  have  elsewhere  indicated  that  the 
various  temperaments  have  some  connec- 
tion with  the  greater  or  lesser  activity  of 
certain  organs  when  compared  with  that  of 
others.  Thus  the  liver  has  within  its  do- 
main the  bilious  temperament.  .  .  .  This 
remark  may  be  applied  to  all  other  organs ; 
each  of  them  is  master  of  the  temperament 
which  it  governs.  .  .  .  Each  organ  has  a 
marked  influence  on  the  solids,  the  vessels, 
the  cellular  tissue  and  the  nerves.  Each 
also  serves  as  a  home  and  laboratory  for  a 
particular  humor  which  it  sends  back  to 
the  blood  after  having  prepared  and  im- 
pregnated it  and  given  it  a  definite  char- 
acter .  .  . 

"I  distinguish  as  many  cachexias,  as 
many  minglings  or  principal  mixtures  of 
humors,  as  there  are  important  organs  and 
distinct  humors.  .  .  .  All  glands  derive 
from  the  cellular  tissues  which  surround 
them  a  large  quantity  of  serosities,  pump- 


CONCEPT  OF  SECRETION       25 

ing  them  on,  to  follow  the  terminology  of 
the  Hippocratic  school.  These  serosities 
mix  with  the  humors  specially  formed  and 
separated  by  the  glands.  Now,  these 
serosities,  not  being  pumped  away  as  they 
should  be,  become  superabundant;  a 
cachexy  that  flows  back  into  the  humors 
and  inundates  all  the  neighboring  parts, 
even  as  the  bile  is  stopped  in  its  course. 
It  is  a  problem  for  physicians  to  trace  and 
classify  the  various  refluxes  that  come  on 
because  of  the  faulty  working  of  some  par- 
ticular organ."10  From  this  it  may  be 
seen  that  the  refluxes  of  which  Bordeu 
speaks  are  not  solely  of  glandular  origin, 
as  Biedl  would  seem  to  have  him  say.  The 
context  of  the  sentence  which  Biedl  cites 
only  goes  to  show  that  the  XVIII  century 
physician  had  crude  views  of  the  possible 
relations  between  secretions  and  patholog- 
ical disorders.  It  is  no  less  curious  to  ob- 
serve— and  this,  above  all,  is  the  object 

10  Th.  Bordeu,  loc.  oit.,  pp.  947-949. 


26     THE  INTERNAL  SECRETIONS 

with  which  I  have  reproduced  the  preced- 
ing quotation,  although  it  is  rather  long — 
that  he  may  be  considered  a  precursor  of 
those  contemporary  pathologists  who  hold 
that  a  certain  morbid  syndrome  may  de- 
pend on  the  hyperactivity  of  the  nervous 
system  which,  in  turn,  is  caused  by  the 
presence  of  an  excessive  amount  of  a  prod- 
uct of  secretion  in  the  blood.  Such  is,  as 
is  well  known,  the  theory  or  vagotonia,  or 
hypertony  of  the  sympathetic  nervous  sys- 
tem, which  is  attributed  by  the  Viennese 
school  to  an  excessive  secretion  of  adren- 
alin. 

In  1845,  J.  Miiller  wrote  in  his  celebrated 
''Text-book  of  Physiology":  "The  duct- 
less glands  are  alike  in  one  particular: 
they  either  produce  a  definite  change  in 
the  blood  which  circulates  through  them,  or 
the  lymph  which  they  elaborate  plays  a 
special  role  in  the  formation  of  blood  or  of 
chyle.  In  every  instance  venous  blood  or 
lymph  are  the  only  substances  which  pass 


CONCEPT  OF  SECRETION       27 

from   the    gland   into    the    general   econ- 
omy." X1 

3.  Here  and  there  in  the  works  of 
several    biologists    of    the    first    part    of 

11  J.  Muller,  ' '  Lehrbuch  der  Physiologie, ' '  1844. 
There  is  a  little  difference  between  this  purely  hypotheti- 
cal statement  and  an  earlier  pronouncement  by  Bur- 
dach:  "The  vascular  or  blood  glands  are  agglomera- 
tions of  vascular  ramifications  united  by  the  primordial 
mass,  which  have  neither  excretory  ducts  nor  an  immedi- 
ate connection  with  the  mucosa  and  which  can  be  con- 
cerned only  in  the  metamorphosis  of  the  blood  without 
the  agency  of  an  external  medium.  This  metamorphosis 
may  occur  as  the  result  of  the  passage  of  the  blood 
through  the  glands,  for  it  is  inconceivable  that  that 
passage  should  be  unattended  by  some  change  in  the 
proportion  of  the  secondary  elements;  or  it  may  result 
from  nutritional  processes  within  the  organs,  or  from 
a  deposit  of  substance  within  their  tissues;  or  it  may 
be  due  to  formation  in  the  tissues  of  a  liquid  which  is 
afterwards  resolved."  (C.  F.  Burdach,  "Traite  de 
physiologie  considered  comme  science  d  'observation. ' ' 
Translated  into  French  by  A.  J.  L.  Jourdan,  Paris, 
Bailliere,  1837-41,  vol.  IV,  p.  83.)  It  is  evident  from 
this  that  it  is  hardly  possible  to  consider  Burdach  and 
Muller  as  the  precursors  of  the  theory  of  internal  secre- 
tion. The  same  may  be  said  in  regard  to  Henle,  Kolli- 
ker,  and  even  more  emphatically  in  regard  to  Bordeu. 
(See:  "Relations  entre  les  organs  a  secretions  internes 
et  les  troubles  de  ces  secretions, ' '  Int.  Congress  of  Medi- 
cine, London,  1913.  Section  Physiology,  Part  I,  pp. 
2-5.) 


28    THE  INTEENAL  SECRETIONS 

the  nineteenth  century  we  note  rare 
allusions  to  the  functions  of  the  vas- 
cular glands.  Thus,  Henle  affirms  that 
these  glands  "have  no  influence  on  ani- 
mal life;  they  may  be  extirpated  or 
they  may  degenerate  without  sensation  or 
motion  suffering  in  the  least,"  and  he 
adds:  "Nothing,  then,  would  be  more 
natural  than  to  assign  them  a  place  among 
the  organs  which  take  part  in  the  chemical 
processes  of  nutrition  or  of  hematosis. 
Many  facts  bear  witness  that  diseases  of 
the  spleen  and  thyroid  are  connected  with 
general  disturbances  in  the  composition 
of  the  blood  and  with  nutritional  dis- 
orders. This  justifies  us  in  thinking  that 
the  blood  undergoes  a  change  in  the  vascu- 
lar glands ;  that  while  it  circulates  through 
their  interior  it  throws  off  certain  sub- 
stances which  undergo  some  sort  of  elab- 
oration in  the  parenchyma,  as  in  the  secre- 
tory glands.  The  difference  consists  in 
this:  that  here  the  products  of  secretion 


CONCEPT  OF  SECEETION       29 

are  not  carried  out  from  the  gland  through 
a  duct  .  .  .,  but  reenter  into  the  blood  ves- 
sels or  lymphatics,  either  by  absorption  or 
exchange  or  by  the  establishment  of  a  tem- 
porary means  of  communication  between 
the  vesicles  and  the  blood  vessels. ' ' 12  But 
it  is  easy  to  see  that  this  is  not  the  distinc- 
tion between  the  two  kinds  of  glands  recog- 
nized by  anatomists,  for  he  differentiated 
them  according  as  to  whether  they  have  or 
do  not  have  ducts  conducting  the  secretions 
to  the  exterior.  Kolliker  says  no  more  about 
it:  "Gewebe  der  Blutgefassdrusen.  Un- 
ter  diesem  Namen  fasst  man  am  passend- 
sten  eine  Reihe  von  Organen  zusammen, 
deren  Uebereinstimmendes  darin  liegt, 
dass  sie  in  einem  besonderen  driisigen 
Gewebe  aus  dem  Blute  oder  anderem  Safte 
gewisse  Stoffe  bereiten,  die  nicht  durch 
besondere   bleibende    or   zeitenweise   sich 

"J.  Henle,  "TraitS  d'anatomie  generate,"  trans- 
lated into  French  by  A.  J.  L.  Joubdan,  Paris,  1843, 
vol.  II,  p.  586. 


30     THE  INTERNAL  SECRETIONS 

bildende  Ausfiihrungsgange  sondern  ein- 
f  ach  durch  Heraussickern  aus  dem  Gewebe 
abgefuhrt  werden  und  dann  in  dieser  oder 
jener  Weise  dem  Organismus  zu  Gute  kom- 
men."  13  Finally,  nothing  further  is  given 
in  the  most  important  contemporary- 
physiological  treatises,  for  example,  those 
by  J.  Miiller,  Longuet,  and  Beclard,  nor  in 
Milne-Edwards 's  great  work,  which  was 
devoted  to  physiology  and  comparative 
anatomy. 

In  all  that  period  there  was  only  a  single 
attempt  at  experimental  investigation, 
that  by  A.  A.  Berthold,  of  Gottingen,14 
who  in  1849  removed  the  testicles  from 
cocks  and  grafted  them  upon  other  parts  of 
their  bodies.  He  observed  that  "the  ani- 
mals retained  their  male  characteristics  in 

14  A.  Kolliker,  "Handbuch  der  Gewebelehre  des 
Menschen, "  p.  74-75,  Leipzig,  1852. 

"Quoted  by  A.  Biedl,  loc.  tit.,  sec.  edit.,  1913,  p.  6. 
Berthold '8  -work  has  been  published  in  the  Archiv  fur 
Physiologie,  1849,  pp.  42-46.  The  experiment  was  only 
carried  out  on  four  cocks. 


CONCEPT  OF  SECRETION       31 

regard  to  voice,  reproductive  instinct, 
fighting  spirit,  and  growth  of  comb  and 
wattles."  From  his  experiments  Berthold 
concluded  that  "the  consensus  is  main- 
tained by  the  productive  influence  of  the 
testicles ;  that  is  to  say,  by  their  effect  on 
the  blood  and,  through  the  blood,  upon  the 
entire  organism."  Biedl  is  therefore  cor- 
rect in  saying  that  "A.  A.  Berthold  was 
the  first  to  demonstrate  experimentally 
the  nature  and  activity  of  a  true  ductless 
gland;  he  showed  the  influence  which  an 
organ  through  which  the  blood  stream  cir- 
culates can  exert  upon  the  composition  of 
the  blood,  and  thus  upon  the  entire  organ- 
ism." With  Biedl  I  will  add,  moreover, 
that  this  discovery,  far  from  attracting 
any  attention,  remained  hidden  in  obscur- 
ity and  hence  had  no  consequences;  it 
stimulated  no  further  research  along  the 
same  lines. 


32     THE  INTERNAL  SECRETIONS 

II.      THE  FOUNDERS  OF  THE  DOCTRINE 

The  true  founders  of  the  doctrine  of  in- 
ternal secretions,  such  as  it  is,  are  Claude 
Bernard  and  Brown-Sequard;  and  in  the 
establishment  of  the  theory  each  played  a 
part  different  from  that  of  the  other. 

1.  I  believe  myself  to  have  been  the  first 
to  bring  to  light,  in  1893,  and  above  all  in 
1897  (loc.  cit.),  the  texts,  often  quoted  since 
then,  showing  that  Claude  Bernard  had 
clear  ideas  about  the  glandular  organs 
which  distribute  their  secretory  products 
by  means  of  the  blood  stream — into  the  in- 
terior part  of  the  body,  as  he  said — and 
these  ideas  came,  indeed,  not  from  infer- 
ences based  on  vague  observations  or  from 
mere  suppositions  and  assumptions 
reached  through  a  priori  reasoning,  but, 
on  the  contrary,  from  a  mass  of  experi- 
mental facts,  solidly  demonstrated.  The 
facts  which  he  used  concern  the  produc- 
tion of  grape  sugar  by  the  liver  and  the 


CONCEPT  OF  SECEETION       33 

passage  of  this  sugar  in  the  hepatic  veins 
and  from  there  into  the  general  circula- 
tion ;  and  once  having  firmly  demonstrated 
the  existence  of  this  internal  secretion,  the 
author  of  this  discovery  is  immediately  led 
to  the  inevitable  generalization:15  "For 
a  long  time  a  false  conception  has  been 
current  as  to  what  a  secretory  organ  con- 
sists in.  It  was  believed  that  all  secretions 
must  be  poured  upon  an  internal  or  ex- 
ternal surface,  and  that  all  secretory  or- 
gans must  necessarily  be  provided  with  an 
excretory  duct  for  the  purpose  of  convey- 
ing to  the  exterior  the  products  of  secre- 
tion. The  case  of  the  liver  establishes  in 
a  most  lucid  manner  that  there  are  internal 
secretions,  i.  e.,  secretions  which,  instead 
of  being  carried  to  the  exterior,  are  dif- 
fused directly  into  the  blood."  Further 
on  (p.  107),  he  says:     "It  is  now  firmly 

15 "Lemons    de    physiologie    exp6rimeutale, "    I,    96, 
Paris,  1855. 


34     THE  INTERNAL  SECRETIONS 

established  that  the  liver  has  two  functions 
of  the  nature  of  secretion.  The  first,  the 
external  secretion,  produces  the  bile,  which 
flows  to  the  exterior ;  the  second,  the  inter- 
nal secretion,  forms  sugar  which  immedi- 
ately enters  into  the  blood  of  the  general 
circulation. ' ' 

Thus  we  see  that  Bernard  clearly  under- 
stood the  functional  significance  of  the 
liver  in  producing  sugar,  and  the  physi- 
ological significance  of  this  sugar,  a  prod- 
uct of  secretion;  and,  at  the  same  time, 
founded  a  new  theory  of  secretion  on  these 
premises. 

This  is  not  all  he  accomplished.  The 
idea,  of  internal  secretion,  which  he  under- 
stood clearly  at  the  very  start  of  his  work, 
appeared  to  be  immediately  connected  in 
his  mind  with  his  conception  of  the  nature 
of  the  blood,  which  he  came  to  consider  as 
the  resultant  of  all  the  internal  secretions. 
"All  the  fluids  which  have  been  examined 


CONCEPT  OF  SECRETION      35 

up  to  the  present  time,"  he  said  in  1859, 16 
' '  are  what  are  known  as  excreted  or  secreted 
fluids,  that  is,  liquids  manufactured  by  or- 
gans which  take  from  the  blood  the  elemen- 
tary substances  necessary  for  the  prepara- 
tion of  the  products  of  their  secretions. 
All  these  organs  pour  their  secretions  out- 
side of  the  blood.  And  there  is  another 
category  of  organs  which  resemble  the 
glandular  organs,  but  differing  from  the 
latter  in  that  they  are  not  provided  with 
excretory  ducts ;  they  must  dispose  of  the 
products  of  their  secretion  into  the  blood 
itself.  These  are  what  we  have  designated 
by  the  term  internal  secretions,  in  order  to 
distinguish  them  from  the  external  secre- 
tions, which  are  not  poured  into  the  blood. 
"I  have  shown  that  the  liver  is,  in  some 
ways,  intermediary,  because  its  secretions 
are  of  both  types;  the  external  secretion 

M"Le§ons  sur  les  proprietes  physiologiques  et  les 
alterations  pathologiques  des  liquides  de  1  'organisme, ' ' 
vol.  II,  pp.  411-412,  Paris,  1859. 


36     THE  INTEENAL  SECEETIONS 

being  represented  by  the  bile  and  the  in- 
ternal by  the  sugar  produced.  The  organs 
whose  mode  of  secretion  are  exclusively 
internal  are  the  spleen,  the  thyroid,  the 
adrenals,  the  lymphatic  ganglia,  etc. 

"  It  is  beyond  all  doubt  that  these  organs 
modify  the  blood  which  passes  through 
them  and  when  leaving  them  contains  sub- 
stances not  present  before  it  entered.  We 
may  therefore  consider  that  the  blood  con- 
stitutes the  sum  total  of  all  these  secretions 
and  it  should,  in  my  opinion,  be  regarded 
as  a  true  product  of  internal  secretion. ' ' 

Bernard  attaches  himself  so  strongly  to 
this  conception  that  we  may  wonder  if  he 
did  not  consider  all  these  organs,  which  he 
classified  among  the  internal  secretory 
glands,  as  blood  forming  organs.  In  his 
lectures  of  1859-60  at  the  College  de 
France,17  he  says:  "The  various  glands 
distributed    throughout    the    entire    body 

17 ' '  Lemons  de  pathologie  experimentale, ' '  2nd  Ed., 
p.  100,  Paris,  1880. 


CONCEPT  OF  SECRETION       37 

must  be  divided  into  two  great  classes: 
those  which  extract  from  the  blood  certain 
particular  principles  which  impart  to  each 
secretion  its  individual  characteristics; 
and  those  which,  on  the  contrary,  appear  to 
secrete  the  blood  itself,  if  I  may  use  the  ex- 
pression, or  those  which  are  intended  to 
enrich  the  circulating  blood  with  products 
manufactured  in  the  interior  of  their  own 
tissues.  Such  are  the  hematopoietic 
glands,  among  which  are  included  the 
spleen,  the  thymus,  the  suprarenal  capsules 
and  other  glands  rich  in  blood  vessels,  and 
which  do  not  possess  excretory  ducts. 
The  lungs,  within  which  the  great  work  of 
oxygenating  the  blood  goes  on,  represent 
the  most  complete  type  of  this  last  variety 
of  gland.  Also  the  liver,  which,  if  we  con- 
sider the  biliary  secretion,  belongs  to  the 
first  class,  is  equally  allied  to  the  second 
group  by  the  glycose  it  produces."  The 
expression  of  Claude  Bernard's  opinions 
on  the  subject  is  in  no  wise  different,  nor 


38     THE  INTERNAL  SECRETIONS 

is  it  more  precise  and  complete  in  his  fa- 
mous "Rapport  sur  les  progres  de  la 
physiologie  generale  en  France";18  I 
have  quoted  the  entire  passage  in  my  study 
in  L'Annee  biologique  of  1897  (p.  315), 
mentioned  above.  It  reads  as  follows: 
"The  secretory  cell  itself  attracts,  creates 
and  elaborates  all  the  products  of  secretion 
which  it  pours  either  on  the  mucous  sur- 
faces without  or  directly  into  the  blood 
stream.  I  have  termed  those  that  flow  to 
the  exterior,  external  secretions,  and  inter- 
nal secretions  are  those  which  are  diffused 
into  the  vital  interior  of  the  body.  .  .  . 
The  internal  secretions  are  far  less  known 
than  the  external.  Their  existence  has 
been  more  or  less  vaguely  suspected  but  is 
not  as  yet  generally  admitted.  However, 
in  my  opinion  their  existence  is  no  longer 
doubtful,  and  I  think  that  the  blood,  or,  in 
other  words,  the  vital  interior  of  the  body, 
must  be  regarded  as  a  product  of  secretion 

18  Paris,  1887,  pp.  73,  79,  83,  84. 


CONCEPT  OF  SECKETION       39 

of  the  internal  vascular  glands.  ...  I  con- 
sider the  liver,  in  the  form  that  it  is  pres- 
ent in  the  higher  vertebrates,  as  a  two-fold 
secretory  organ.  It  combines,  in  reality, 
two  distinct  methods  of  secretion,  and  it 
represents  two  secretions :  The  first  is  the 
biliary  secretion,  which  is  external  and 
flows  through  the  bile  duct  into  the  intes- 
tine ;  the  second  is  the  internal  secretion  of 
glycogen  and  is  poured  into  the  blood 
stream.  .  .  .  That  part  of  the  liver  which 
secretes  glycogen  is  composed  of  a  large 
vascular  gland,  i.  e.,  a  gland  which  has  no 
external  excretory  duct.  In  it  are  pro- 
duced the  sugar  constituents  of  the  blood, 
perhaps  also  other  albuminoid  prod- 
ucts. But  there  exist  many  other  vascular 
glands,  such  as  the  spleen,  the  thyroid,  the 
suprarenal  capsules  and  the  lymphatic 
glands,  the  functions  of  which  are  as  yet 
unknown.  However,  these  organs  are  gen- 
erally regarded  as  playing  some  role  in  the 
regeneration  of  the  blood  plasma,  as  well 


40     THE  INTERNAL  SECRETIONS 

as  in  the  formation  of  the  red  and  white 
corpuscles  which  float  in  this  liquid." 

To  sum  up,  we  owe  to  Claude  Bernard 
the  first  direct  demonstration 19  of  an  in- 
ternal secretion — the  passage  into  the 
blood  of  sugar  formed  in  the  liver — and 
the  general  conception  of  these  secretions, 
which  he  understood  as  serving  to  main- 
tain the  composition  of  the  blood. 
Throughout  his  entire  work  I  find  no  text 
which  would  seem  to  indicate  that  he 
meant  anything  else  by  the  expression 
secretions  internes  than  the  concept  he  first 
expressed,  viz.,  that  they  serve  to  maintain 
the  composition  of  the  blood.  How  differ- 
ent this  is  from  the  true  conception !  How 
remote  are  the  ideas  represented  by  this 
expression  to-day  from  those  held  by 
Claude  Bernard!  A  word  has  no  more 
meaning  than  the  thought  it  expresses. 

2.  In  order  to  grasp  the  exact  value  of 

w  Berthold  's  experiment,  mentioned  by  Biedl,  only 
constitutes  an  indirect  proof. 


CONCEPT  OF  SECRETION       41 

the  ideas  that  Claude  Bernard  introduced 
into  medical  science,  it  is  necessary  to  state 
that  absolutely  no  interest  was  aroused  by 
his  work.  And  it  is  curious  to  note  in  this 
connection  how  very  differently  scientific 
ideas  fare  with  Fortune.  Some,  notwith- 
standing that  they  are  based  on  insuffi- 
ciently demonstrated  premises  and  hasty 
deductions,  at  times  have  a  rapid  and  bril- 
liant rise  to  fame ;  others,  though  securely 
based  on  a  sure  foundation,  remain  in 
oblivion  for  long  periods  or  are  slow  to  at- 
tract and  retain  attention,  until  they  are 
finally  resurrected  by  the  light  of  fame. 
The  doctrine  of  Claude  Bernard  under  dis- 
cussion belongs  to  the  latter  category.  I 
am  well  aware  that  the  theory  of  the  glyco- 
gen-producing  function  of  the  liver  was 
assailed  and  severely  criticized  by  many 
physiologists  for  many  years;  but  it  was 
also  very  much  admired  and  amply  veri- 
fied by  many  others,  so  that,  in  quite  a 


42     THE  INTERNAL  SECRETIONS 

short  space  of  time,  its  acceptance  was 
forced  upon  physiologists,  with  the  excep- 
tion of  several  rebellious  spirits,  as  Lon- 
get.20  And  beginning  with  1855,  the  year 
in  which  the  "Legons  de  physiologie  ex- 
perimentale "  appeared,  considerable  work 
was  produced  which  would  naturally  be 
coordinated  with  the  experiments  on  the 
glycogen  normally  produced  by  the  liver. 
I  refer  to  the  researches  of  Brown-Sequard 
on  the  physiology  of  the  suprarenal  cap- 
sules (1856-58) ; 21  the  observations  of  Vul- 
pian  (1856)  on  the  coloring  matter  of  the 

20 See  the  last  (third)  edition  of  Longet's  "Traits 
de  physiologie,"  Paris,  1867-69,  reprinted  1873,  vol.  II, 
pp.   290-296. 

21  It  is  important  to  recall  that  Brown-Sequard,  in 
his  first  manuscript  (Arch.  gen.  de  med.,  1856),  wrote 
very  clearly:  "The  absence  of  the  secretions  of  the 
suprarenal  glands  is  therefore  more  rapidly  fatal  than 
the  suppression  of  the  urinary  secretion  ..."  "The 
question  of  the  function  of  the  suprarenal  capsules 
therefore  depends  on  the  following:  What  are  the  sub- 
stances which,  when  carried  to  these  glands  by  the  blood, 
are  there  modified,  and  what  are  the  products  of  this 
modification  which  are  carried  away  by  the  blood  when 
it  leaves  the  capsules?" 


CONCEPT  OF  SECRETION       43 

medullary  substance  of  the  suprarenal 
capsules  and  the  passage  of  this  matter 
into  the  venous  blood  of  the  capsules ; 22 
SchifT's  researches  on  the  connection  of 
the  spleen  with  the  digestive  (proteolytic) 
function  of  the  pancreas  (1862).  But  no 
one  coordinated  these  facts,  not  even 
Claude  Bernard.  This  would  be  most  sur- 
prising were  it  not  called  to  mind,  in  ac- 
cordance with  what  I  have  just  shown, 
what,  in  reality,  was  his  conception  of  the 
nature  of  the  "internal  secretions."  It  is 
therefore,  possible  that  it  was  this,  some- 
what narrow,  conception  which  concealed 
from  him  the  general  connection  existing 

"Vulpian  had  well  noted  the  general  interest  of  this 
statement:  "I  always  noted  that  the  droplet  of  san- 
guineous liquid  issuing  from  the  venous  orifice  (of  the 
capsular  vein  in  the  sheep  in  Vulpian's  experiments) 
produced  the  indicated  reaction  with  sesquiehlorid  of 
iron.  This  proves  for  the  first  time,  and  in  a  most  de- 
cisive manner,  the  hypothesis  which  regards  the  supra- 
renal capsules  as  being  like  the  glands  termed  vascular, 
i.  e.,  glands  pouring  their  products  of  secretion  directly 
into  the  blood"  (C.  K.  de  I'Acad.  des  sc,  Sept.  27,  1856, 
XLIII,  663). 


44     THE  INTERNAL  SECRETIONS 

between  these  newly  discovered  facts  and 
the  normal  glycemia. 

Towards  the  end  of  that  period,  how- 
ever, there  came  a  biologist  who  under- 
stood the  importance  of  the  question. 
"The  action  of  the  glands  which  do  not 
have  excretory  ducts,"  says  Charles 
Robin,23  "can  only  be  studied  from  the 
physiological  point  of  view.  The  nature 
of  the  products  of  this  action  can  only  be 
definitely  established  by  the  comparison 
of  the  arterial  blood  with  the  venous  blood 
that  leaves  these  organs,  or  by  comparing 
the  ingoing  lymph  with  that  which  has  al- 
ready passed  through  the  gland.  Unfor- 
tunately, the  direct  comparative  analysis 
of  the  liquids  which  these  organs  receive 
and  those  which  issue  from  them  has  not 
been  done  anywhere  in  a  suitable  manner ; 
no  more  than  it  has  been  done  with  the 

28  Ch.  Eobin,  ' '  Legons  sur  les  humeurs  normalea  et 
morbides,"  2nd  Ed.,  Paris,  J.  B.  Bailliere  et  fils,  1874, 
p.  316. 


CONCEPT  OF  SECEETION       45 

secreting  parenchyma  cells  themselves." 
Further  on,24  Robin  writes:  "Each  of 
these  various  glands  furnishes  one  or  more 
special  principles  of  its  own  to  the  blood 
carried  away  by  the  corresponding  vein  to 
the  principal  organ  to  which  it  is  con- 
nected. Just  as  the  blood  which  enters  the 
liver  does  not  contain  the  sugar  which  the 
departing  fluid  holds,  it  is  likewise  found 
that  the  formation  of  the  substances  which 
are  most  certainly  found  in  the  returning 
blood  must  be  attributed  to  the  tissues  of 
the  vascular  glands,  which  have  poured 
them  into  the  blood  exactly  as  the  liver  un- 
burdens itself  of  sugar  into  the  hepatic 
veins. ' ' 

1 '  These  facts  are  quite  closely  associated 
with  the  study  of  the  constitution  of  the 
blood   and  lymph.25     The   studies   of   M. 

»ma.,  p.  318. 

*  It  is  thus  to  be  seen  that  this  idea  of  the  constitu- 
tion of  the  blood  and  lymph  is  always  dominant.  It  is 
found  in  Liegeois  ("Anatomie  et  physiol.  des  glandes 
vasculaires  sanguines,"  Paris,  1860), as  is  proved  by  the 


46     THE  INTERNAL  SECRETIONS 

Claude  Bernard  support  them,  he  having 
given  the  name  of  internal  secretions  to 
the  products  poured  into  the  blood  itself 
by  the  vascular  glands,  in  order  to  distin- 
guish them  from  the  external  secretions, 
the  products  of  which  are  deposited  with- 
out the  blood."  In  a  note  he  adds:  "As 
far  back  as  1837,  furthermore,  Burdach, 
who  considered  the  spleen,  thyroid,  supra- 
renal capsules  and  thymus  as  agglomera- 
tions of  vascular  ramifications,  thought 
that  the  vascular  glands  could  only  serve 
for  what  he  termed  the  metamorphosis  of 
blood."     Great  as  was  the  authority  of 

following  passage:  "Prom  all  these  experiments 
(Liegeoia  has  just  cited  Vulpian's  experiments  on  the 
suprarenal  venous  blood  and  those  of  Beclard,  Funke, 
Lehmann,  and  Gray  on  the  splenic  venous  blood),  we 
have  the  manifest  result  that  in  the  spleen  and  the 
suprarenal  capsules,  modifications  take  place  which 
change  the  constitution  of  the  blood"  (loc.  cit.,  p.  53). 
"The  vascular  glands,"  says  Liegeois  further  (p.  59), 
' '  have  for  their  principal  function  pouring  into  the  cir- 
culation materials  which  change  the  microscopic  and 
chemical  constitution  of  the  blood."  Moreover,  this 
work  lacks  facts  and  also  a  critical  spirit. 


CONCEPT  OF  SECEETION       47 

Charles  Robin  at  that  time,  above  all  in 
France,  these  considerations,  supported  by 
those  of  Bernard,  in  his  "Rapport  sur  les 
progres  de  la  physiologie  generale  en 
France,"  did  not  stir  many  to  a  clear  re- 
alization of  their  value,  or  provoke  any  ex- 
perimental researches. 

A  little  later  we  again  find  the  term  "in- 
ternal secretions,"  from  the  pen  of  Paul 
Bert.26  "These  are,"  he  says,  "products 
of  secretion  which  are  emptied  into  the 
blood. " 27  To  this  he  adds  nothing  but 
these  lines  (p.  254) :  "The  liver  gives  us  an 
example  of  a  gland  which  not  only  manu- 
factures a  liquid  destined  to  be  expelled, 
but  also  substances  which  are  poured  into 
the  blood. ' '  So  brief  is  this  notice  that  we 
would  be  justified  in  thinking  that  Paul 
Bert   did  not   appreciate   the  importance 

36 "Lemons  de  zoologie,"  Paris,  G.  Masson,  1881. 
This  was  a  work  written  with  a  view  to  the  secondary 
instruction  of  young  girls.  I  am  indebted  to  Prof.  V. 
Pachon  for  indicating  to  me  this  source. 

27  Loc.  cit.,  p.  248. 


48     THE  INTERNAL  SECRETIONS 

of  the  question  from  the  point  of  view  of 
general  physiology,  did  we  not  reflect  that 
the  work  in  which  it  occurs  is  an  elemen- 
tary textbook. 

Several  years  after  the  death  of  Claude 
Bernard,  Schifr*  published  his  great  work 
' '  On  the  effects  of  the  removal  of  the  thy- 
roid body, " 28  a  labor  inspired  by  the  ob- 
servations of  J.  L.  and  A.  Reverdin  (1883) 
and  Kocher  on  postoperative  myxedema 
(1883),  which  recalled  in  a  most  striking 
manner  the  experiments  of  two  English 
physicians,  W.  Gull  (1872)  and  W.  W.  Ord 
(1878),  on  spontaneous  myxedema.  It  is 
known,  further,  that  Schiff  in  1859  had  al- 
ready pointed  out  several  of  the  successive 
accidents  of  thyroidectomy.  Did  he  in- 
clude the  thyroid  among  the  vascular 
glands?  He  puts  the  question  thus :  "We 
may  wonder  if  the  thyroid  body  produces 
in  its  interior  ...  a  substance  which  it  de- 

M  Revue  mSdicale  de  la  Suisse  romande,  Feb.  15  and 
Aug.  15,  1884. 


CONCEPT  OF  SECRETION      49 

livers  to  the  blood  stream  and  which  con- 
stitutes a  nutritive  element  for  another  or- 
gan (nervous),  or  whether  it  acts  mechan- 
ically by  its  anatomical  position.  To  de- 
cide between  these  two  alternatives,  it  is 
necessary  to  find  a  means  of  transplanting 
it,  by  grafting  it  into  another  part  of  the 
body.  If,  after  this  has  been  done,  the 
accidents  resulting  from  its  removal  are 
avoided  or  reduced  to  a  minimum,  it  is  evi- 
dent that  the  action  of  the  thyroid  is  due  to 
its  composition  and  not  to  its  anatomical 
relations;  this  will  prove  the  thyroid  to 
have  a  chemical  function.  ..."  He  then 
states  that  the  grafts  he  attempted  disap- 
peared by  resorption ;  nevertheless  the  ani- 
mals in  which  the  thyroid  body  was  trans- 
planted suffered  from  less  severe  effects, 
from  which  he  concludes  that  "the  sub- 
stance of  the  grafted  organs,  taken  up 
by  the  blood,  serves  to  counterbalance  the 
untoward  effects  of  thyroidectomy." 
"It  would  be  curious  to  investigate  if 


50     THE  INTERNAL  SECRETIONS 

the  macerated  extract  of  the  thyroid,  in- 
troduced into  a  serous  cavity,  or  injected 
into  the  rectum,  has  the  same  immunizing 
power. ' ' 29  This  is  all  that  is  said.  Schiff 
did  not  attempt,  in  the  presence  of  all  these 
facts,  to  connect  them  with  what  was  al- 
ready known  about  the  suprarenal  cap- 
sules and  the  formation  of  grape  sugar  in 
the  liver.  As  I  have  said  elsewhere : 30 
"Schiff,  although  always  so  close  to  the 
work  of  Claude  Bernard,  and  whose  inves- 
tigations on  the  connections  between  the 
function  of  the  spleen  and  the  digestive  ac- 
tivity of  the  pancreas  furnish  some  of  the 
most  favorable  arguments  for  the  doctrine 
of  internal  secretions,  never  even  used 
these  terms." 

3.  Since  the  time  of  Brown-Sequard 
everything  has  been  changed.  The  notion 
of  internal  secretions  has  spread  every- 

29  Several  years  later  this  experiment  was  carried  out 
by  Gr.  Vassale  and  myself,  independently  of  one  another. 

80  E.  Gley,  "Essais  de  philosophic  et  d'histoire  de  la 
biologie, "  p.  255,  Paris,  Masson  and  Co.,  1900. 


CONCEPT  OF  SECRETION       51 

where,  is  understood  and  accepted 
throughout,  although  its  significance  has 
changed  in  some  respects.  It  is,  in  fact, 
possible  that  Brown-Sequard  retained  the 
conception  introduced  into  science  by 
Claude  Bernard;  namely,  the  realization 
that  the  glands  "without  external  secre- 
tion ' '  have  a  special  influence  on  the  blood, 
inasmuch  as  they  secrete  substances  neces- 
sary to  its  constitution;  he  even  adds  that 
the  tissues  play  this  role  of  "blood  modi- 
fiers." But  he  did  not  stop  at  this  point. 
By  his  experiments  on  the  therapeutic 
action  of  testicular  extract,31  and  by  the 
generalization  he  induced  concerning  the 

■  Brown-Sequard,  "Des  effets  produits  chezl'homme 
par  des  injections  sous-cutanees  d'un  liquide  retire  des 
testicules  frais  de  cobaye  et  de  chien. "  (C.  B.  de  la 
Soc.  de  biol,  June  13,  1889,  XLI,  pp.  415-449)  ;  "Second 
note  sur  les  effets  produits  chez  l'homme  par  des  in- 
jections sous-cutanees  d'un  liquide  retire  des  testicules 
frais  de  cobaye  et  de  chien"  (Ibid.,  pp.  420-422).  The 
origin  of  Brown-Sequard 's  researches  on  the  thera- 
peutic effects  of  extracts  of  the  genital  glands  is  to  be 
found  in  these  two  initial  communications  which  were 
received  with  derisive  skepticism. 


52     THE  INTERNAL  SECRETIONS 

analogous  action  of  other  organic  extracts, 
he  was  led  to  the  idea  that  many  organs 
secrete  into  the  blood  principles  which 
have  the  property  of  acting  in  an  elective 
manner  on  neighboring  or  distant  organs. 
"We  have  called  attention  .  .  ."he  says, 
"to  a  new  method  of  therapy  which  con- 
sists in  the  use  of  subcutaneous,  intraperi- 
toneal or  intravenous  injections  of  special 
principles  obtained  by  the  maceration  .  .  . 
of  one  or  another  of  the  glandular  organs 
of  the  body.  We  find  in  a  note  relating  to 
our  communication  published  by  M.  Gley 
facts  confirming  our  ideas  on  one  of  the 
vascular  glands,  the  thyroid.  .  .  . 

"All  the  tissues,  in  our  opinion,  modify 
the  blood  by  an  internal  secretion  taken  up 
by  the  venous  blood.  From  this  conclusion 
it  necessarily  follows  that,  if  the  subcuta- 
neous injection  of  the  juices  extracted  from 
these  tissues  produces  only  inadequate  ef- 
fects, it  is  necessary  to  inject  the  venous 
blood  of  these  parts  under  the  skin.  .  .  . 


CONCEPT  OF  SECEETION       53 

"We  admit  that  each  tissue  and,  more 
generally,  each  cell  of  the  organism,  se- 
cretes for  its  own  use  special  products,  or 
ferments,  which  are  poured  into  the  blood 
and  which  influence,  through  the  inter- 
mediary agency  of  this  liquid,  and  not 
through  the  mechanism  of  the  nervous  sys- 
tem, all  the  other  cells,  thus  rendering  all 
of  them  mutually  interdependent. ' ' 32  The 
last  sentence  is  characteristic  and  contains 
the  germinal  form  of  the  entire  theory  of 
functional  correlations  of  humoral  origin, 
or  of  a  chemical  nature,  as  we  say  to-day. 
"These  particular  soluble  products," 
writes  Brown-Sequard  further,33  "pene- 
trate into  the  blood  and  influence,  through 
the  intermediary  action  of  this  liquid,  the 

82 Brown-Sequard  and  D'Arsonval,  "Additions  a 
une  note  sur  1 'injection  des  extraits  liquides  de  divers 
organs  comme  methode  therapeutique"  (C.  E.  de  la  Soc. 
de  bioh,  April  25,  1891,  XLIII,  265-68). 

33  Brown-S£quard  and  D  'Arsonval,  ' '  Eecherches  sur 
les  liquides  retires  des  glandes  et  d'autres  parties  de 
l'organisme  et  sur  leur  emploi,  en  injections  sous- 
cutanSes  comme  methode  therapeutique"  (Arch,  de 
physiol,  1891,  5th  series,  III,  491-506;  see  p.  496). 


54     THE  INTERNAL  SECRETIONS 

other  cells  of  the  anatomical  elements  of 
the  organism.  The  result  of  this  is  that 
the  various  cells  of  the  economy  thus  form 
a  solidarity,  and  this  is  accomplished  by  a 
mechanism  other  than  that  of  the  nervous 
system."  "All  the  tissues — glands  or 
other  organs — have  special  internal  secre- 
tions and  thereby  give  to  the  blood  some- 
thing other  than  the  products  of  their 
nutritive  disassimilation.  The  internal  se- 
cretions, either  by  a  direct  favorable  influ- 
ence, or  by  preventing  the  occurrence  of 
noxious  reactions,  seem  to  be  of  great 
value  in  maintaining  the  organism  in  its 
normal  state. ' ' 34 

Brown-Sequard  added  to  the  doctrine  of 
Claude  Bernard  the  notion  of  the  action  of 
"specific  substances"  secreted  into  the 
blood-stream  by  the  various  organs  and, 
as  a  consequence  of  this,  the  no  less  impor- 
tant concept  of  functional  humoral  corre- 
lations.   This  greatly  enriched  the  theory 

8*  Arch,  de  physiol.,  1891,  5th  series,  III,  506. 


CONCEPT  OF  SECRETION       55 

of  internal  secretions.  And  hence  the 
reason  why  Brown-Sequard  is  called  the 
founder  of  the  doctrine  of  internal  secre- 
tions. It  is  certain  that,  had  the  concept 
of  internal  secretion  not  already  existed, 
these  new  ideas,  as  I  have  already  men- 
tioned,35 could  never  have  come  to  life,  and 
from  this  point  of  view  there  is  a  direct 
connection  of  Claude  Bernard  to  Brown- 
Sequard,  but  the  latter  certainly  discov- 
ered something  new ;  he  took  a  long  stride 
in  advance,  a  step  in  the  determination  of 
the  causes  of  the  functional  mechanism. 

Certainly,  the  study  undertaken  by  him 
on  the  dynamogenic  influence  of  testicular 
extract  is  imperfect — I  showed  why  in 
1897  36 — and  does  not  constitute  a  good  ex- 
ample of  the  action  of  these  "special  inter- 
nal secretions"  whose  importance  he  fore- 
saw. 

^"Traite  Slementaire  de  physiol.,"  p.  1143,  Paris, 
1900. 

88  Loc.  cit.,  Annie  biologique. 


56     THE  INTERNAL  SECRETIONS 

This  example  was  soon  furnished  by  the 
researches  of  Gr.  Vassale  (1890)  and  Gley 
(1891)  3T  on  the  amelioration  of  the  grave 
disorders  resulting  from  complete  thy- 
roidectomy in  the  dog  by  injections  of  thy- 
roid extract,  as  well  as  the  application  of 
this  method  to  the  treatment  of  myxe- 
dema (by  G.  R.  Murray,  1891,  followed  by 
many  other  physicians).  It  was  then  no 
longer  possible  to  doubt  the  sound  founda- 
tions of  Brown-Sequard's  views  on  the 
role  of  internal  secretions  in  "maintaining 
the  normal  state  of  the  organism,"  or  in 
reestablishing  that  normal  state  when  it 
is  altered  by  disease.    This  was  the  more 

87 1  will  avoid  overburdening  these  pages  with  biblio- 
graphical notes  by  advising  the  reader  to  refer  to  A. 
Biedl's  work — capital  for  the  study  of  the  internal 
secretions — where  they  will  be  found  easily  ("Innere 
Sekretion,"  Berlin  and  Vienna,  Urban  and  Schwarzen- 
berg,  1910;  2nd  Ed.,  1913),  or  also  two  articles  by 
Swale  Vincent,  "Innere  Sekretion  und  Driisen  ohne 
Ausf uhrungsgang "  (Ergebnisse  der  Physiol.,  1910,  IX, 
pp.  455-586,  and  1911,  XI,  pp.  218-327).  I  will  naturally 
give  references  which  are  not  given  in  these  two  bibliog- 
raphies or  which  are  not  easy  to  discover  there  rapidly. 


CONCEPT  OF  SECRETION       57 

strongly  established  several  years  later 
when  there  appeared  the  experiments  of 
G.  Glover  and  E.  A.  Schafer  (1894-1895) 
which  immediately  attracted  attention. 
Also  the  work  of  N.  Cybulski  and  Szmono- 
vicz  (1895),  J.  P.  Langlois  (1897),  W.  H. 
Howell  (1898),  etc.,  on  the  action  of  supra- 
renal extract  on  the  cardiovascular  sys- 
tem; those  of  N.  Cybulski  (1895),  J.  P. 
Langlois  (1897),  A.  Biedl  (1898),  G.  P. 
Dreyer  (1899),  etc.,  on  the  action  of  the 
venous  blood  of  the  suprarenal  capsules 
and  the  numerous  observations  relative  to 
the  reduction  in  the  intensity  of  metabolism 
in  myxedema,  or  conversely,  the  increase 
in  the  metabolic  activities  of  the  body  un- 
der the  influence  of  preparations  of  thy- 
roid extract  or  iodothyrin.  Finally,  it  is 
of  importance  to  recall  that  at  the  time 
when  Brown-Sequard,  in  1889-1890,  was 
giving  such  an  impulse  to  the  theory  of 
internal  secretions,  J.  von  Mering  and  0. 
Minkowski  discovered  the  important  role 


58     THE  INTERNAL  SECRETIONS 

that  the  pancreas  plays  in  the  metabolism 
of  sugar,  and  many  immediately  attacked 
the  problem  from  other  angles  and  showed 
that  these  changes  in  the  carbohydrate 
metabolism  are  due  to  an  internal  secre- 
tion of  the  pancreas  (R.  Lepine,  1889, 
1891 ; 38  E.  Gley,  1891 ; 39  E.  Hedon,  1892 ; 40 
Vaughan  Harley,  1892  ;41  0.  Minkowski, 
1892; 42  J.  Thiroloix,  1892  43). 

3SB.  Lupine,  "Nouvelle  theorie  du  diabete"  (Lyon 
mid.,  Dec.  29,  1889,  LXII,  p.  621);  "La  pathogenie 
du  diabete"  (Bevue  scient.,  Feb.  28,  1891,  p.  273); 
"Sur  la  question  du  ferment  glyeolytique  "  (C.  B.  de 
la  Soc.  de  oiol,  April  25,  1891,  XLIII,  271).  Lepine 
was  the  first  to  write  the  words  "pancreatic  internal 
secretion. ' ' 

39  E.  Gley,  "Sur  les  troubles  consecutifs  a  la  destruc- 
tion du  pancreas"  (C.  B.  de  I' Acad,  des  sc,  April  6, 
1891,  CXII,  752);  "Les  decouvertes  recentes  sur  la 
physiol.  du  pancreas"  (Bev.  gen.  des  sc.,  July  30,  1891, 
469-76). 

40  E.  Hedon,  "Diabete  experimental"  (Nouveau 
Montpelier  med.,  Jan.  2,  1892,  p.  27). 

41 V.  Haeley,  "Pathogenesis  of  Pancreatic  Diabetes" 
(Brit.  Med.  Jour.,  Aug.  27,  1892). 

aBerl.  Min.  Wchs.,  Feb.  1,  1892. 

43  J.  Thieoloix,  "Etude  sur  les  effets  de  la  suppres- 
sion lente  du  pancreas"  (Mem.  de  la  Soc.  de  biol.,  Oct. 
22,  1892,  XLIV). 


CONCEPT  OF  SECRETION       59 

I  have  therefore  not  exaggerated  the 
part  played  by  Brown-Sequard  in  repre- 
senting him  as  one  of  the  founders  and  the 
resurrector  of  the  theory  of  internal  secre- 
tion. Such  is  also  the  opinion  of  numer- 
ous physiologists.  I  will  only  quote  that 
of  Biedl,  one  of  those  who  has  studied  the 
question  most  completely:  "In  establish- 
ing the  doctrine  of  internal  secretions, 
Brown-Sequard  has  opened  to  physiology 
a  new  and  fertile  field  of  research,  he  has 
paved  the  way  to  the  comprehension  of 
many  morbid  disorders  and  has  shown  us 
a  method  of  therapeutics  which  is  both  ra- 
tional and,  in  many  cases,  remarkably  suc- 
cessful."44 

III.       THE   PRESENT    CONCEPTION   OP  INTERNAL 
SECRETION 

From  the  initial  works  which  followed 
the  publications  of  Brown-Sequard  from 
1889  to  1891,  it  was  easy  to  see  how  rapidly 

**Loc.  cit.,  p.  6. 


60     THE  INTERNAL  SECRETIONS 

the  notion  of  specific  functional  excitants 
of  glandular  origin  would  develop.  The 
original  idea  of  Claude  Bernard,  that  of 
glandular  products  modifying  the  compo- 
sition of  the  blood,  on  the  contrary,  made 
no  progress  at  all.45  The  ideas  of  Brown- 
Sequard  having  been  experimentally  veri- 
fied, as  he  had  foreseen,  are  taking  posses- 
sion of  physiology  and  penetrating  into 
pathology.  It  may  be  said  that  these  ideas 
have  not  as  yet  been  set  forth  with  great 
precision  and  that  they  lack  the  neces- 
sary support  of  numerous  and  thoroughly 
studied  facts.  But  they  are  quickly  ac- 
quiring this  precision  while  facts  are  rap- 
idly accumulating  which  give  them  both 

"It  might  be  maintained — though  vainly — that  the 
two  ideas  can  be  confused,  in  the  sense  that  from  the 
passage  into  the  blood  of  active  specific  products  com- 
ing from  certain  glands,  there  would  result  an  actual 
modification  in  the  composition  of  this  liquid.  However, 
Claude  Bernard's  sole  idea  seems  to  have  been  that  this 
modification  is  of  a  chemical  nature.  The  new  notion, 
since  added,  is  that  of  the  specific,  elective  power  of 
various  products  of  glandular  origin.  This  is  properly 
a  physiological  idea. 


CONCEPT  OF  SECRETION       61 

solidity  and  a  wide  scope.  And  the  new 
knowledge  is  of  an  entirely  new  sort. 
"What  there  is  characteristic  about  this," 
I  said  in  1897,46  "is  that  we  are  now  deal- 
ing with  functional  actions  which  have 
neither  cause,  nor  reason,  nor  an  end  of 
their  own;  but  each  one  of  these  acts  de- 
pends on  another  physiological  action,  and 
this  dependence  appears  to  be  always  of  a 
chemical  nature,  be  it  direct  or  indirect, 
being  accomplished  through  the  intermedi- 
ary action  of  the  nervous  system.  It  is 
found,  for  example,  that  a  substance 
formed  at  a  certain  point  in  the  organism 
is  of  such  composition  that  it  constitutes 
the  excitant  adapted  to  stimulate  action  in 
another  organ."  The  same  year,  in  the  re- 
port that  I  was  charged  with  presenting 
to  the  XII  International  Congress  of  Medi- 
cine, at  Moscow,  on  the  pathological  physi- 
ology of  myxedema,  I  wrote:  "Nothing 
can  convince  us  that  iodothyrin  has  not  a 

*  L'AnnSe  bid.,  p.  330. 


62     THE  INTERNAL  SECRETIONS 

direct  influence  on  the  metabolism.  If, 
therefore,  the  thyroid  gland,  atrophied  or 
attacked  by  some  form  of  degeneration,  no 
longer  secretes  that  substance,  nutritional 
disorders  promptly  follow,  due  only  to  the 
organism's  lack  of  a  principle  which  nor- 
mally augments  the  intensity  of  the  meta- 
bolic processes.  And  thus  the  regulation 
of  the  intracellular  chemical  phenomena 
appears  to  us  as  possibly  of  a  directly 
chemical  nature.  There  exist  substances 
which  enhance,  others  that  moderate,  these 
phenomena.  Through  the  elective  action 
of  these  bodies,  nutritional  equilibrium 
must  be  mechanically  arrived  at.  Iodo- 
thyrin  is  one  of  these  substances.  .  .  .  Are 
not  the  ferments  secreted  by  the  pancreas, 
which  regulate  the  production  of  sugar  by 
the  liver  and  the  oxydizing  ferments  .  .  . 
similar  substances,  acting  in  the  same  di- 
rect manner  on  the  anatomical  elements? 
.  .  .  Furthermore,  are  there  not  still  other 
substances,  as  the  one,  probably  from  the 


CONCEPT  OF  SECRETION       63 

genital  organs,  which,  according  to  the  in- 
genious experiments  of  Mironoff,  stimu- 
lates the  secretion  of  milk  at  the  necessary 
time,  independently  of  all  action  of  the 
nervous  system?"  Two  years  later,  in 
1899,  I  qualified  with  "specific  glandular 
products"  the  "substances  which  result 
from  the  normal  activity  of  many  glands 
and  which  appear  to  play  a  considerable 
part  in  the  regulation  of  the  circulation. 
.  .  .  Many  have  in  fact  been  led,  since  we 
have  understood  the  great  importance  of 
the  internal  secreting  glands,  to  investi- 
gate if  small  quantities  of  the  products  of 
these  glands,  which  pass  at  different  times 
or  continuously  into  the  blood,  do  not  ex- 
ercise a  more  or  less  important  influence 
on  the  vasomotor  centers. 

".  .  .  The  fact  that  substances  of  gland- 
ular origin,  endowed  with  a  stimulating 
or  depressing  cardiovascular  action,  are 
normally  found  in  the  blood,  shows  that 
they  play  an  important  part  in  the  regula- 


64     THE  INTERNAL  SECRETIONS 

tion  of  the  blood  pressure ;  and  as  the  ac- 
tivity of  the  glandular  organs  often  varies 
in  an  abnormal  manner,  being  either  exces- 
sively increased  or  diminished  and  some- 
times even  suppressed,  the  regulation  of 
the  circulation  may  be  proportionately  dis- 
turbed. Herein  lies  an  indispensable  labor 
to  be  undertaken;  namely,  the  determina- 
tion of  the  relations  which  exist  between 
the  normal  variations  of  the  circulation, 
and  more  especially  between  the  blood 
pressure  and  functions  of  the  glands  like 
the  adrenals,  the  thyroid,  etc.,  the  quantity 
of  active  principles  they  send  out  at  vari- 
ous times  or  continuously  into  the  blood, 
and  the  conditions  which  are  antagonistic 
to  the  action  of  these  substances.  .  .  . 

"From  all  these  facts  it  follows  that  the 
tone  of  the  muscles  of  the  blood  vessels,  in 
so  far  as  it  depends  on  an  automatic  stimu- 
lation, either  direct  or  indirect,  is  main- 
tained not  only  by  nervous  stimulation,  va- 
riations in  the  gases  contained  in  the  blood 


CONCEPT  OF  SECRETION       65 

and  by  the  products  of  the  katabolic  proc- 
esses, but  also  by  specific  substances  nor- 
mally formed  in  various  glands. " 47  To 
specific  functional  excitants  in  general, 
Starling  gave,  in  1905,  the  happy  name  of 
hormones   (from  op/xaw,  I  excite). 

The  notion  of  specific  functional  exci- 
tants, or  hormones,  led  quite  naturally  to 
that  of  functional  correlations  of  humoral 
cause.  Because  these  same  "special  solu- 
ble products, ' '  as  Brown-Sequard  said,  are 
poured  into  the  blood  and  "influence  the 
other  cells  of  the  organism,"  these  cells 
"are  thus  rendered  into  a  solidarity — act- 
ing in  unison — and  by  some  mechanism 
other  than  the  action  of  the  nervous  sys- 
tem" (Brown-Sequard,  see  above).  Many 
occupied  themselves  with  determining 
these  functional  correlations  of  a  chemical 
nature,  connecting  them  with  one  another 

47  E.  Gley,  "Meeanisme  physiologique  des  troubles 
vasculaires"  (in  "Traite  de  Path,  gen."  by  Ch.  Bou- 
chard, III,  133-211;  see  pp.  165-172). 


66     THE  INTERNAL  SECRETIONS 

and  at  the  same  time  differentiating  them 
from  the  correlations  of  nervous  origin,  al- 
ready studied  for  many  years.  It  was  also 
recognized  that  there  are  still  others,  which 
form  an  intermediary  class,  the  neuro- 
chemical correlations,  or  functional  mani- 
festations provoked  by  nervous  action,  this 
nervous  action  determining  a  chemical  ex- 
citation which  is  carried  to  some  part  of 
the  nervous  system.48 

During  this  time  investigations  followed 
one  another,  in  which  facts  relative  to  the 
internal  secretions  and  the  action  of  these 
on  the  organism  and  its  functions  were  ex- 
amined and  classified.  In  proportion  as 
they  multiplied,  the  facts  assumed  their 
true  value  and  their  meaning  became  more 
precise.49 

48  This  is  the  classification  which  I  presented  to  my 
classes  of  1908-1909  in  the  College  of  France  and  that 
I  have  adopted  for  the  outline  study  of  functional  cor- 
relations that  is  given  in  my  "Traite  elementaire  de 
physiologie,"  Paris,  1906-1909,  p.  1142;  2nd  Edit.,  1910, 
p.  1167;  3rd  Edit.,  1913,  p.  1181. 

**It  would  not  be  out  of  place  to  cite  here  the  first 


CONCEPT  OF  SECRETION       67 

While  the  work  on  functional  correla- 
tions just  indicated  was  being  carried  out, 

of  these  studies  as  well  as  the  most  important  of  those 
which  were  published  later: 

E.  Abelous,  "La  physiologie  des  glandes  a  secretion 
interne,  corps  thyroide  et  capsules  surrSnales"  (Bevue 
gin.  des  sc,  May  15,  1893,  IV,  273-278)  ;  E.  Hedon, 
"Les  travaux  regents  sur  la  physiol.  des  glandes  vascu- 
laires  sanguines"  (Nouveau  Montpellier  Medical,  1893, 
II,  467-468) ;  E.  A.  Schafer,  "On  Internal  Secretions" 
{Lancet,  Aug.  10,  1895,  321-324);  E.  Gley,  "Expose 
des  donnees  experimentales  sur  les  correlations  fonc- 
tionelles  chez  les  animaux"  (L' Annie  biol.,  1897,  I,  313- 
330) ;  "  Le  neo-vitalisme  et  la  physiologie  g^nerale ' ' 
{Bevue  scient.,  March  4,  1911,  257-265) ;  W.  H. 
Howell,  "Internal  Secretions  Considered  in  their 
Physiological,  Pathological  and  Clinical  Aspects" 
(Trans,  of  the  Congress  of  American  Physicians  and 
Surgeons,  1897,  IV,  70-86);  H.  C.  Wood,  "The  Ductless 
Glands"  (Amer.  Journ.  of  Med.  Sc,  1897,  CXIII,  505- 
13);  Francis  P.  Kinnicutt,  "The  Therapeutics  of  the 
Internal  Secretions"  (Ibid.,  1897,  CXIV,  1-23);  James 
P.  Putnam,  "The  Clinical  Aspects  of  the  'Internal 
Secretions'  "  (Ibid.,  1898,  CXV,  31-49);  H.  Boruttau, 
"Tiber  den  jetztigen  Stand  unserer  Kentnisse  von  den 
Functionen  der  Blutgef  assdriisen  "  (Deutsch.  med. 
Woch.,  Sept.  21,  1899,  XXV,  625-27) ;  E.  de  Cyon,  "Les 
glandes  regulatrices  de  la  circulation  et  de  la  nutrition" 
(Bevue  gin.  des  sc,  Sept.  30,  1901,  XII,  828-35);  "Die 
Gefassdriisen  als  Regulatorische  Schutzorgane  des  Zen- 
tralnerven  systems, "  Berlin,  J.  Springer,  1910;  A. 
Biedl,  "Innere  Sekretion"  (Wiener  Klinik,  1903, 
XXIX,  281-283);  "tiber  innere  Sekretion"   (Verhandl. 


68     THE  INTERNAL  SECRETIONS 

the  nature  of  the  humoral  excitants  was 
more  completely  determined. 

der  Gesellschaft  deutscher  Natur for scher  und  Aertzte, 
1911);  C.  E.  de  M.  Sajous,  "The  Internal  Secretions 
and  the  Principles  of  Medicine,"  Philadelphia,  1903; 
G.  Coronedi,  ' '  Secrezioni  interne  e  loro  chimismo" 
(Arch,  di  fisiologia,  1904,  II,  36-59);  W.  M.  Bayliss 
and  E.  H.  Starling,  "The  Chemical  Correlation  of  the 
Secretory  Process"  (Proceedings  of  the  Royal  Soc, 
1904,  LXVII,  310-322);  E.  H.  Starling,  "The  "Chemi- 
cal Correlation  of  the  Functions  of  the  Body,"  Croonian 
Lectures,  June,  1905  (The  Lancet,  1905)  ;  A.  Magnus- 
Levy,  "  Organ therapie  und  Innere  Sekretion"  (Berlin, 
1906,  pamphlet  of  40  pages);  "Der  Stoffwechsel  bei 
Erkrankungen  einiger  Driisen  ohne  Ausfuhrgang"  (in 
"Handbuch  der  Pathol,  des  Stoffwechsels, "  1907,  II, 
311-354);  Swale  Vincent,  "Internal  Secretion  and  the' 
Ductless  Glands"  (Lancet,  August  11  and  18,  1906); 
"The  Ductless  Glands"  (Science  Progress,  January, 
1909);  L.  Fredericq,  "De  la  coordination  organique 
par  action  chimique"  (Scientia,  1909,  vol.  V,  Third 
year) ;  L.  Hallion,  ' '  Les  f onctions  de  secretion  in- 
terne" (Bevue  scientifique,  May  8,  1909,  583-588);  C. 
Parhon  and  M.  Golstein,  "Les  secretions  internes" 
(Paris,  A.  Maleine,  1909) ;  A.  Pi  y  Suner,  "  Correlationes 
fisiologicas "  (Association  espanola  para  el  progreso  de 
las  sciencias,  Valencia,  1910);  S.  J.  Meltzer,  "Animal 
Experimentation  in  Eelation  to  our  Knowledge  of  Se- 
cretions, Especially  Internal  Secretions"  (Proc.  of  the 
Pathol.  Soc.  of  Philadelphia,  Sept.,  1910,  N.  S.,  XIII, 
170-196);  I.  Ott,  "Internal  Secretions  from  a  Physi- 
ological and  Therapeutic  Standpoint"  (Philadelphia,  E. 
D.  Vogel,  1910);  G.  Fano,  "La  coordinazione  umorale" 


CONCEPT  OF  SECRETION       69 

"The  exciting  substances  mentioned," 
says,  for  example,  Starling,50  "so  far  as 
they  are  known  to  us,  are  not  assimilable 
and  exert  a  dynamic  influence  on  the  liv- 
ing cells.  In  this  respect  they  are  analo- 
gous to  substances  which  form  the  usual 
remedies  of  our  pharmacopeias.  Since  it 
is  their  role  to  be  frequently  excreted,  in 
virtue  of  a  normally  organic  function,  into 
the  circulatory  system  by  which  they  are 
conducted  to  each  of  the  organs  on  which 
they  exercise  their  specific  action,  they  can- 
not therefore  belong  to  that  class  of  com- 
plex compounds,  animal   or  vegetable  in 

(Atti  delta  Soc.  Italiana  por  il  progresso  delle  sc, 
Naples,  Oct.,  1910)  ;  R.  G.  Hoskins,  ' '  The  Interrelation 
of  the  Organs  of  Internal  Secretion ' '  (Amer.  Jour,  of 
Med.  Sciences,  March  and  April,  1911). 

For  original  views  or  remarks  filled  with  new  in- 
formation, see  above  all  the  works  of  Bayliss  and 
Starling,  E.  de  Cyon,  G.  Fano,  E.  Gley,  S.  J.  Meltzer 
and  E.  H.  Schafer.  To  this  list  must  naturally  be 
added  Biedl's  book  and  Swale  Vincent's  two  studies 
(in  "Ergebnisse  der  Physiol."),  mentioned  above. 

00  Address  delivered  at  the  meeting  of  the  Gesellschaft 
Deutscher  Naturforscher  und  Aerzte,  Stuttgart,  1906. 


70     THE  INTEENAL  SECRETIONS 

origin,  which  we  term  toxins."  And 
through  the  study  of  the  remarkable  prop- 
erties of  several  of  these  exciting  sub- 
stances (Reizstoffe,  hormones),  as  for  ex- 
ample the  active  principle  of  thyroid, — 
iodothyrin  1 — adrenalin  and  secretin,  physi- 
ology has  discovered  an  entirely  new  field 
of  investigation,  which  is  as  yet  far  from 
being  completely  explored. 

Pathology  did  not  fail  to  participate  con- 
siderably in  all  these  researches  and  the 
progress  of  our  knowledge  of  the  endo- 
crine glands.  Some  important  contribu- 
tions by  pathologists  helped  directly  in  the 
upbuilding  of  the  doctrine  of  internal  se- 
cretions. Let  us  but  recall  what  those  who 
labored  to  raise  this  doctrine  obtained  from 
the  observations  of  Lancereaux  (1877-79) 
on  the  pancreas  in  diabetes  and  the  pro- 
found studies  of  diabetes  in  its  relations  to 
lesions  of  the  pancreas,  beginning  with  the 
researches  of  J.  von  Mering  and  Minkow- 
ski   (1889-90) ;  from  the  comparison    (P. 


CONCEPT  OF  SECRETION       71 

Semon,  1884)  between  the  description  of 
the  clinical  phenomena  of  myxedema  made 
by  English  clinicians,  and  the  obser- 
vations of  Swiss  surgeons,  J.  and  A.  Rev- 
erdin,  Kocher,  on  post-operative  myxe- 
dema, as  well  as  the  effects  of  thyroid  med- 
ication on  this  syndrome ;  from  the  patho- 
logical anatomy  of  acromegaly;  from  Ad- 
dison's disease  and  the  study  of  the  toxic 
effects  of  adrenalin,  etc.  What  a  light  is 
thrown  by  physiological  experiments  on  all 
these  clinical  and  anatomo-pathological 
facts,  and  how,  reciprocally,  the  latter 
strengthen  the  conclusions  arrived  at 
through  animal  experimentation!  Medi- 
cine has  drawn  its  profits  from  this  co- 
operation of  physiology  and  pathology: 
hemophilia  is  explained;  many  of  the 
anomalies  of  growth  are  also  elucidated; 
the  pathogeny  of  diabetes  is  cleared  up; 
the  pathology  of  the  thyroid  apparatus  has 
been  worked  out;  that  of  the  hypophysis 
and  thymus  undertaken  with  success;  the 


72     THE  INTERNAL  SECRETIONS 

discovery  and  definition  of  new  syndromes 
in  which  the  suprarenal  capsules  or  repro- 
ductive glands  are  concerned.  Such  is  the 
sum  total  of  the  main  acquisitions  acquired 
through  this  work.  "The  following  two 
factors,"  Meltzer  says  rightly,51  "are  re- 
sponsible, I  believe,  for  the  marvelous 
progress  of  this  new  branch  of  experimen- 
tal medicine.  In  the  first  place,  the  recent 
investigations  on  the  ductless  glands  were 
carried  out  purely  by  biological  methods 
of  research.  The  second  factor  is  to  be 
found  in  the  important  fact  that  these  in- 
vestigations had  the  great  advantage  of 
an  harmonious  cooperation  of  critical  ani- 
mal experimentation,  scientific  clinical  ob- 
servations and  the  intelligent  analysis  of 
surgical  results."  There  is  an  underlying 
reason  for  this  cooperation,  which  I  re- 
called in  my  Report  on  Myxedema  at  the 
XII  International  Congress  of  Medicine  at 
Moscow,  to  wit:     "For  the  savant,"  as 

"Loc.  tit.,  p.  171. 


CONCEPT  OF  SECEETION       73 

Claude  Bernard  said,  "  neither  medicine 
nor  physiology  is  distinct;  there  is  only 
one  science  of  life,  there  are  only  the  phe- 
nomena of  life  which  must  be  explained, 
in  the  pathological  state  as  well  as  in  the 
physiological."52 

"Claude   Bernard,   "Introduction   a   l'etude   de   la 
medecine  experimental, ' '  p.  257,  Paris,  1865. 


n 


DISTINCTIVE  CHARACTERISTICS  OF  THE  INTER- 
NAL. SECRETORY  GLANDS  AND  THE  PRINCIPAL. 
PRODUCTS  OF   THEIR  ACTIVITIES 


II 


DISTINCTIVE  CHARACTERISTICS  OF  THE  INTER- 
NAL SECRETORY  GLANDS  AND  THE  PRINCIPAL 
PRODUCTS   OF  THEIR  ACTIVITIES 

Knowledge  of  the  nature  and  functions 
of  the  internal  secretory  glands  can  only 
be  based  on  the  precise  determination  of 
the  conditions  which  make  of  these  glands 
a  special  system,  and  then  on  the  discov- 
ery of  the  distinctive  characteristics  of  the 
products  resulting  from  the  activities  of 
these  organs.  Herein  lies  the  primary  and 
fundamental  problem. 

I.       CONDITIONS    ESSENTIAL    TO    INTERNAL 
SECRETION 

Three  conditions  suffice  to  determine  an 
internal  secretion  as  such,  but  these  three 
conditions  are  absolutely  necessary:    The 

77 


78     THE  INTERNAL  SECRETIONS 

first  is  of  an  histological  nature ;  the  second 
results  from  chemical  considerations;  and 
the  third  is  of  a  physiological  order.  That 
is,  the  cells  of  the  vascular  glands  in  ques- 
tion must  present  the  characteristics  of 
granular  elements  and  these  elements 
must  be  in  close  relation  to  the  efferent 
vessels  of  the  organ;  in  these  cells  and  in 
the  venous  blood  of  the  gland  or  in  the 
efferent  lymph,  a  specific  substance  must" 
be  chemically  determined;  finally,  the  ve- 
nous blood  of  the  gland  must  have  the 
physiological  action  and  properties  of  this 
specific  substance.1 

Undoubtedly,  for  many  of  the  organs  in- 
cluded  among   the   endocrine   glands,   all 

1  For  technical  reasons  which  are  easily  understood, 
the  investigation  of  specific  products  in  the  lymph  is 
even  more  difficult  than  in  the  blood.  Up  to  the  present, 
we  have  only  been  able  to  determine  the  presence  of 
specific  substances  in  the  venous  blood  of  some  glands; 
on  the  other  hand,  the  attempts  that  it  has  at  times 
been  possible  to  make  on  the  lymph  have  always  resulted 
negatively.  (A.  J.  Carlson  and  A.  Woelfel,  "On  the 
Internal  Secretion  of  the  Thyroid"  (Amer.  Jour,  of 
Physiol,  1911,  XXVI,   32-67);    A.   J.   Carlson  and  F. 


CHARACTERISTICS  OF  GLANDS     79 

these  conditions  have  not  been  satisfied. 
Several  of  the  latter  category  are,  however, 
most  certainly  such  glands,  even  to  the 
most  exacting  critic.  In  the  case  of  these 
glands,  in  lien  of  all  the  conditions  men- 
tioned above,  we  have  a  collection  of  facts 
which  permits  us  to  recognize  them  as  en- 
docrine glands.  In  science  as  in  all  human 
activities,  we  cannot  always  follow  implic- 
itly the  dictates  of  logic.  No  one  would 
think,  for  example,  of  contesting  the  right 
of  the  thyroid  gland  to  a  position  among 
the  endocrine  glands,  although  there  has 
not  as  yet  been  discovered  in  the  venous 
blood  of  that  organ  any  specific  chemical 
or  physiological  property  (Carlson,  Cor- 
onedi,  Cunningham,2  Gley).     But  so  spe- 

M.  Drennan,  "The  Alleged  Discharge  of  the  Internal 
Secretion  of  the  Pancreas  into  the  Lymph"  (Proc.  of 
the  Soc.  for  Exper.  Biol,  and  Med.,  1914,  XI,  71-72). 
This,  however,  is  no  reason  why  we  should  not  recog- 
nize, as  does  R.  Lepine  (Revue  de  Medecine,  Feb.  10, 
1914,  XXXIV,  p.  81-88),  that  it  would  undoubtedly  be 
interesting  to  undertake  studies  of  this  sort. 

*  Cunningham  has  unsuccessfully  used  as  much  as  30 


80     £HE  INTERNAL  SECRETIONS 

cific  are  the  effects  of  extirpation  of  this 
organ  and  so  characteristic  is  the  action  of 
thyroid  extract  in  counterbalancing  the 
harmful  effects  of  this  deficiency,  that  we 
are  forced  to  admit  that  substances  con- 
tained in  thyroid  extract  have  an  elective 
influence  on  the  internal  medium.3 

By  an  analogous,  but  not  as  yet  so  well 
founded,  compromise,  we  are  led  to  con- 
sider the  spleen  and  the  thymus  as  internal 
secretory  organs,  the  reasons  being  purely 
physiological :  The  spleen  because  it  fur- 
nishes the  blood  passing  through  it  with  a 
substance  which  transforms  trypsinogen 
into  active  trypsin,  as  was  shown  by  the 
experiments  of  A.  Herzen  (1888,  1893) ; 4 

to  50  cc.  of  thyroid  venous  blood  for  the  investigation 
of  an  action  on  the  arterial  pressure.  Further  mention 
of  this  work  of  Cunningham  will  be  found  on  p.   216. 

3  See  also  p.  111. 

4  A.  Herzen,  "Appunti  di  chimiea  fisiologiea"  (An- 
nali  di  chim.  med.  e  farm.,  1888,  VIII,  IV  series,  Tor- 
ino);  "Rate  et  Pancreas"  (C.  B.  de  la  Soc.  de  biol., 
July  29,  1893,  XLV,  pp.  814-817).  Herzen's  opinion 
finds  support  in  the  experiments  of  Lafayette  B.  Men- 
del and  Leo  F.  Rettgeb,  (Am.  Jour,  of  Physiol.,  1902, 


CHARACTEEISTICS  OF  GLANDS     81 

the  thymus  because  its  extirpation  results 
in  disordered  development  of  the  skeleton 
(experiments  of  K.  Basch,  1896;  Cozzo- 
lino,  1903;  Sommer  and  Floerken,  1908; 
Ugo  Soli,  1909 ;  M.  Lucien  and  J.  Parisot, 
1910) ;  and,  furthermore,  because  in  cas- 
trated animals  the  thymus  is  larger  (A. 
Calzolari,  1898  ;5  J.  Henderson,  1904;  Ugo 
Soli,  1906  and  1909),  while  in  animals  whose 
thymus  has  been  removed,  the  develop- 
ment of  the  male  genital  glands  is  arrested 
(Ugo  Soli,  1909 ).6  But  the  spleen  and  the 
thymus  are  neither  histologically  nor  em- 

VII,  387-404),  who  have  stated  that  injections  of  splenic 
venous  blood  increase  the  proteolytic  power  of  the  pan- 
creas. The  defibrination,  it  is  true,  might  be  a  cause 
of  error,  if  we  admit  that  the  destruction  of  the  leuco- 
cytes liberates  kinase.  But  this  objection  can  be  an- 
swered by  recalling  Gachet's  experiments  (in  Paehon's 
laboratory,  These,  Bordeaux,  1897) — which  were  nega- 
tive— with  defibrinated  arterial  and  venous  blood. 

8  The  thymus,  according  to  Calzolari,  diminishes  in 
weight  at  puberty,  when  the  generative  organs  begin  to 
function. 

9  Noel  Paton  (1904)  has  obtained  results  which  are 
the  reverse  of  these;  that  is,  an  increase  in  weight  of 
the  testicles  after  thymectomy. 


82     THE  INTERNAL  SECRETIONS 

bryologically  glandular  organs;  they  are 
hemolymphoid  in  nature.  With  this  reser- 
vation, we  may  state  that  they  discharge 
into  the  blood  products  akin  to  the  internal 
secretions. 

(1)  Histological  Conditions.  —  Al- 
though without  any  relation  to  the  ex- 
terior, being  without  excretory  ducts,  the 
glands  called  vascular,  internal  secretory 
or  endocrine,  are  penetrated  by  numerous 
blood  vessels  with  which  their  cellular  ele- 
ments are  in  intimate  connection  and  into 
which  they  deposit  their  secretion. 

Exceptions  are  the  liver  and  the  pan- 
creas, which  are  provided  with  excretory 
canals,  but  which  are  also  glands  of  inter- 
nal secretion;  their  cells,  so  to  speak,  are 
pointed  in  two  directions,  towards  the  ex- 
cretory canals  and  towards  the  blood  ves- 
sels. 

We  find  the  same  double  orientation  in 
the  duodenojejunal  mucous  membrane,  the 
cells  of  which  discharge  a  digestive  juice 


CHARACTERISTICS  OF  GLANDS     83 

into  the  intestinal  cavity,  i.e.,  to  the  ex- 
terior, but  they  also,  under  certain  con- 
ditions with  which  we  are  thoroughly  ac- 
quainted, deliver  to  the  blood  the  sub- 
stance which  stimulates  the  pancreas  to  se- 
cretion, namely,  secretin.  Moreover,  we 
may  remark  that  it  is  not  as  yet  known 
definitely  how  secretin  is  formed  and 
whether  this  substance  is  really  a  product 
of  glandular  origin.  Furthermore,  it  is 
not  only  in  its  role  of  secretin  producer 
that  the  pancreas  behaves  like  an  endo- 
crine gland;  it  is  also  an  absorbing  organ. 
The  histological  process  of  the  absorption 
of  fats  consists  in  intraprotoplasmic  elabo- 
ration; in  other  words,  it  is  a  secretory 
process,  and  perhaps  this  is  no  less  true 
of  the  absorption  of  albuminoid  substances. 
These  are  the  products  of  the  decomposi- 
tion of  those  materials  which  reach  the  in- 
testinal mucous  membrane  on  its  free  side, 
and  the  cells  of  this  membrane  deliver,  by 


84     THE  INTERNAL  SECRETIONS 

their  internal  side,  fats  and  perhaps  also 
albuminoids  to  the  blood. 

It  is  also  not  without  reason  that  R. 
Heidenhain,  Oppel,  Pfluger  and  others 
have  compared  the  phenomena  of  absorp- 
tion to  those  of  secretion.  In  fact,  as  sev- 
eral histologists  have  shown,  the  epithelial 
layer  of  the  intestine  behaves  like  a  true 
granular  element;  it  is  a  "granular  ele- 
ment with  two  surfaces,"  physiologically 
speaking.  Through  its  cavitary,  or  exter- 
nal, surface,  it  receives  and  elaborates  the 
materials  to  be  absorbed;  through  its  in- 
ternal side  pass  out,  after  having  been 
elaborated,  the  materials  which  then  pass 
into  the  vascular  or  lymphatic  circulation. 
These  two  acts  undoubtedly  take  place,  re- 
spectively, in  the  supranuclear  and  infra- 
nuclear  zones  of  the  cell.  The  physiologi- 
cal polarity  of  the  cell  imputes  a  morpho- 
logical bipolarity  and  also  the  presence,  in 
both  zones  alike,  of  the  organisms  indis- 
pensable to  glandular  secretion.     This  ap- 


CHARACTERISTICS  OP  GLANDS     85 

pears  to  be  verified  by  the  observation 
which  shows  the  same  mitochondrial  for- 
mations in  both  zones,  while  the  ordinary 
glandular  cell  is  only  provided  with  one  of 
them.  (Champy.7)  Absorption  is  thus 
only  a  particular  case  of  the  general  proc- 
ess of  secretion.  And  the  essential  re- 
sult of  this  secretion — the  formation  and 
passage  into  the  blood  of  the  specific  al- 
bumins of  the  plasma  8 — is  of  the  highest 
importance.  "We  may  say,"  Champy  re- 
marks 9  ' '  that  the  intestinal  epithelium  se- 
cretes the  plasma, — the  internal  medium, — 
or  at  least  the  principal  part  of  it,  and  it 
is  indeed  the  most  highly  differentiated  se- 
cretion of  the  organism,  for  this  internal 

7  A.  Peenant  and  P.  Bouin,  "Traite  d 'histologie, ' ' 
vol.  II,  p.  823,  Paris,  1911. 

8  It  is  known  that  the  role  of  the  intestinal  wall  in 
the  formation  of  the  proteid  substances  of  the  blood 
plasma  can  not  actually  be  considered  as  beyond  ques- 
tion. 

8  Ch.  Champy,  ' '  Kecherches  sur  1  'absorption  intestinale 
et  le  role  des  mitochondries  dans  1 'absorption  et  la 
secretion"  (Arch,  d'anat.  microscopique,  1911,  XIII, 
55-170). 


86     THE  INTERNAL  SECRETIONS 

medium  is  to  the  highest  degree  specific." 
There    are,    therefore,    glands    with    a 
double  secretory  function,  external  and  in- 
ternal. 

We  can  make  still  another  distinction 
between  the  various  endocrine  glands,  and 
one  which  is  not  devoid  of  interest  from 
the  point  of  view  of  the  physiological  sig- 
nificance of  these  organs.  It  has  been  dem- 
onstrated that  the  cells  of  the  choroid 
plexuses  are  granular  cells  the  activity  of 
which  regulates  the  composition  of  the  ce- 
rebrospinal fluid,10  contained  in  the  cere- 

10  J.  W.  Findlay,  "The  Choroid  Plexuses  of  the  Lat- 
eral Ventricles  of  the  Brain,  Their  Histology,  Normal 
and  Pathological"  (Brain,  1897,  XXII,  161-203);  J. 
Galeotti,  "Studio  morfologico  e  citologico  della  volta 
del  diencefalo  in  alcuni  vertebrati"  (Biv.  di  patol.  ner- 
vosa e  mentale,  1897,  ii,  480-517) ;  H.  Obeesteiner, 
"Anleitung  beim  Studium  des  Baus  der  nervosen  Cen- 
tral-organe  im  gesunden  und  kranken  Zustande, "  Fourth 
edition,  pp.  651-53.  Leipzig  and  Vienna,  1901 ;  A.  Pettit 
and  J.  Gieard,  "Processus  secretaires  dans  les  cellules 
de  revetement  des  plexus  choro'ides  des  ventricules  lat- 
eraux,  consecutifs  a  1 'administration  de  muscarine  et 
d 'ether"  (C.  B.  de  la  Soc.  de  Uol.,  July  27,  1901,  LIII, 
825);  "Sur  la  fonction  secretaire  et  la  morphologie  des 


CHARACTERISTICS  OF  GLANDS     87 

bral  ventricles  and  in  the  central  canal  of 
the  spinal  cord.  And  it  is  known,  further- 
more, that  the  cerebrospinal  fluid  thus 
formed  returns  to  the  blood  by  the  peri- 
vascular sheaths  (lymphatic  path)  and  the 
blood  vessels  of  the  dura  mater.  This 
cerebrospinal  fluid,  first  secreted  into  an 
exterior  cavity,  and  then  reabsorbed,  is  an 
example  of  an  externo-internal  secretion; 
and  it  might  be  said  that  the  choroid 
plexuses  are  glands  of  external  secretion, 
but  having  an  internal  destination  (A.  Pet- 
tit  and  J.  Girard).11 

Conversely,  there  are  internal  secretory 
glands  having  an  external  destination,  or, 
in  other  words,  there  are  interno-extemal 
secretions.12    A  typical  member  of  this  last 

plexus  choroides  des  ventricules  lateraux  du  systeme 
nerveux  central"  {Arch,  d'anat.  microscopique,  1902,  V, 
213-264)  ;  F.  K.  Studnicka,  ' '  Unters.  iiber  den  Bau 
des  Ependyms  der  nervosen  Centralorgane "  (Anat. 
Hefte,  1900,  pp.  303-431). 

u  This  means  that  the  secretion,  made  on  the  exterior, 
is  intended  to  be  reabsorbed. 

12  Biedl  has  used  a  somewhat  indefinite  name — negative 


88     THE  INTERNAL  SECRETIONS 

class  is  urea,  formed  in  the  liver,  excreted 
into  the  blood  and  taken  up  by  the  kid- 
neys to  be  eliminated  to  the  exterior.  Such 
also  are  the  phenylsulphates,  if  we  admit 
that  they  are  formed  in  the  liver;  there 
are  also  substances  excreted  into  the  he- 
patic blood  and  intended  for  ultimate  renal 
excretion.  No  matter  which  gland  is  in 
question,  whether  properly  internal  or 
mixed  (having  a  double  secretion,  inter- 
nal and  external),  or  a  transitory  external 
secretion  (an  external  secretion  having  an 
internal  destination,  mentioned  above),  or 
a  transitory  internal  secretion  (finally  des- 
tined for  the  exterior),  there  is  not  one 
with  cellular  elements  which  can  not  be 
characterized  as  glandular.  In  all  these 
cells  the  nucleus  and  a  part  of  the  proto- 
plasm (upper  mitochondrial  protoplasm, 
or  ergastoplasm)  participate  in  the  elabo- 
ration  of  the   secretory  products  in  the 

internal  secretion — for  such  a  secretion.  Swale  Vincent 
has  also  used  this  terminology. 


CHAEACTERISTICS  OF  GLANDS     89 

same  manner  as  in  the  cells  of  the  glands 
that  have  been  best  studied  histologically. 

In  brief,  it  is  the  morphological  condi- 
tion— cellular  structure  and  relations  of 
the  cells  to  the  blood  vessels — that  is  best 
satisfied  by  the  endocrine  glands. 

(2)  Chemical  Condition.  —  Every 
product  of  secretion  is  a  cellular  differen- 
tiation, the  morphological  expression  of  a 
chemical  elaboration.  This  differentiation 
is  a  result  of  cytoplasmic  activity;  the 
product  must  be  recognizable  by  certain 
chemical  characteristics,  both  in  the  glan- 
dular cell  itself  and  outside  of  it.  This 
means,  in  the  case  of  an  internal  secretion, 
which  is  what  we  are  primarily  concerned 
with  at  present,  that  the  products  of  se- 
cretion must  be  found  in  the  efferent  blood 
of  each  gland. 

The  presence  of  the  products  of  secre- 
tion in  the  glandular  cells  has  only  excep- 
tionally been  demonstrated.  It  has  been 
shown,  indeed,  that  there  are  fat  globules 


90     THE  INTERNAL  SECRETIONS 

in  the  intestinal  cells  and  in  the  cells  of 
adipose  bodies,13  and  that  adrenalin  exists 
in  the  suprarenal  cells ;  in  the  thyroid  cells, 
it  is  true,  the  presence  of  a  complex 
product  of  colloid  matter  has  been  demon- 
strated, but  do  we  know  if  this  colloid  mat- 
ter contains  only  the  active  principle  of 
the  secretion,  or  if  it  contains  at  all  the 
active  principle1? 

Likewise,  only  in  a  small  number  of  in- 
stances have  the  specific  principles  of  the 
endocrine  glands  been  identified  chemically 

"Although  the  adipose  bodies  are  not  made  up  of 
epithelial  cells,  the  adipose  cell  is  nevertheless  a  glandu- 
lar cell  and  has  the  closest  connection  with  its  capillary 
plexus.  This  undoubtedly  explains  the  ease  with  which 
deposits  of  fat  are  accumulated  when  the  organism  has 
need  of  them,  as,  for  example,  in  jaundice.  The  follow- 
ing observation  furnishes  a  very  clear  proof  of  this  fact 
and  at  the  same  time  of  the  glandular  nature  of  adi- 
pose bodies:  Prenant  has  seen  mitochondria  formed 
in  three  days  throughout  the  protoplasm  in  the  cells  of 
adipose  bodies  in  the  nape  of  the  neck  of  kittens  ren- 
dered athreptic  by  defective  alimentation;  the  cell  was 
thus  brought  back  to  its  initial  condition  and  all  the  fat 
disappeared  from  it,  being  collected  in  the  vessels. 
(Prenant  told  me  this  interesting  fact  by  word  of 
mouth.) 


CHARACTERISTICS  OF  GLANDS     91 

in  the  venous  blood  of  a  given  internally 
secreting  organ.  Fatty  bodies  have  been 
found  and  even  quantitatively  determined 
in  the  veins  of  the  intestine  and  in  the  tho- 
racic duct ;  in  the  blood  of  the  hepatic  veins 
glycose  and  urea  have  been  found,  and  in 
the  blood  of  the  suprarenal  vein,  adrena- 
lin. 

Numerous  chemical  investigations  of  the 
products  of  internal  secretion  are  in  prog- 
ress at  the  present  time.  This  research 
must  ultimately  lead  to  the  determination 
of  what  these  substances  are,  what  is  their 
nature  and  therapeutic  value.  In  fact,  with 
the  exception  of  the  products  which  serve 
as  nutritive  materials  (glycose,  fats,  spe- 
cific albumins),  the  products  intended  for 
excretion  (as  urea)  and  finally  adrenalin, 
our  knowledge  of  the  chemical  properties  of 
these  bodies  is  very  limited.  The  most  in- 
teresting from  this  point  of  view,  as  well  as 
from  the  physiological  standpoint,  appear 
to  be  the  bodies  of  synthetic  intracellular 


92      THE  INTERNAL  SECRETIONS 

origin,  as  adrenalin.  Bnt,  for  the  present 
moment,  this  is  the  only  one  known;  in 
spite  of  the  efforts  of  A.  Ostwald,  of  Zu- 
rich, we  are  not  yet  sure  if  his  iodothyro- 
globulin  is  the  active  principle  of  the  thy- 
roid gland.  Likewise,  the  chemical  nature 
of  secretin  is  as  yet  unknown. 

(3)  Physiological  Condition.  —  That 
the  physiological  condition  be  fulfilled,  we 
must  find  a  specific  substance  in  the  ef- 
ferent blood  of  a  gland,  as  demonstrated 
by  the  physiological  properties  of  this 
blood,  collected  and  injected  in  variable 
quantities  into  another  animal.  Further- 
more, this  specific  substance  must  remain 
for  a  sufficient  period  of  time  in  the  gen- 
eral circulation,  since,  to  reach  a  more  or 
less  distant  organ  on  which  it  acts,  it  is 
necessary,  at  least  in  the  majority  of  cases, 
that  the  active  product  secreted  passes 
with  the  efferent  blood  of  the  gland  into 
the  blood  of  the  general  circulation.  It 
is  all  the  more  necessary  that  its  presence 


CHARACTERISTICS  OF  GLANDS     93 

be  speedily  demonstrated,  inasmuch  as 
these  glandular  products,  diffused  through- 
out the  blood  stream,  may  very  quickly 
lose  their  activity,  either  through  exces- 
sive dilution,  or  as  a  result  of  a  process 
of  destruction  as  is  the  case,  for  example, 
with  adrenalin  (see  p.  215).  Their  exist- 
ence in  the  general  circulation  may  there- 
fore be  so  short,  or  they  may  be  so  minute 
in  quantity,  as  to  appear  without  any 
physiological  significance.  To  this  it 
could  be  objected,  of  course,  that  this  sub- 
stance, soon  after  entering  the  arterial 
blood,  does  not  remain  there,  but  fixes  it- 
self onto  the  organs  on  which  it  acts,  this 
fixation  being  the  condition  for  its  action. 
Hence  the  difficulty  of  finding  these  sub- 
stances in  sufficient  quantity  at  a  given 
moment  in  the  arterial  blood.  One  could, 
in  any  case — provided  he  was  assured 
of  their  physiological  destination — detect 
them  in  the  blood  of  the  left  heart.  Only 
the   physiological   destination   of   the   se- 


94      THE  INTERNAL  SECRETIONS 

creted  product  gives  the  true  significance 
of  a  secretion  (see  p.  149).  Now,  in  so 
far  as  the  internal  secretions  are  con- 
cerned, this  destination  is  marked  by  the 
passage  of  a  specific  substance  from  the 
venous  blood  of  the  gland  into  the  general 
circulation,  and  it  is  only  the  physiological 
properties  of  this  venous  blood,  tempo- 
rarily acquired  by  the  blood  in  general, 
that  attest  it. 

To  recapitulate,  the  essential  proof  of 
an  internal  secretion — in  addition  to  the 
clinical  proof,  when  this  is  available  (see 
below) — is  the  physiological  proof,  that  is 
to  say,  the  demonstration  of  the  physio- 
logical properties  of  a  specific  glandular 
product  transferred  in  a  more  or  less  dur- 
able form  to  the  blood.  This  is,  together 
with  the  chemical  proof,  whenever  the  lat- 
ter can  be  given,  the  essential  proof  of  an 
internal  secretion;  and  it  is  perhaps  the 
most  important  for  physiologists  and 
pathologists.    Far  from  having  been  fur- 


CHARACTEEISTICS  OF  GLANDS     95 

nished  for  all  the  endocrine  glands,  its 
investigation,  on  the  contrary,  has  been 
very  much  neglected. 

1.  The  physiological  demonstration  has 
been  given  for  the  glands  which  elaborate 
the  substances  that  modify  chemical  proc- 
esses and  act  in  the  manner  of  diastases. 
One  of  these  substances,  that  derived  from 
the  spleen,  serves  to  activate  a  ferment,14 
although  the  mechanism  by  which  this  is 
accomplished  is  not  known;  another,  that 
derived  from  the  pancreas,  favors  a  proc- 
ess of  assimilation,  and  we  are  still  dis- 
cussing  by   what    mechanism    this    takes 

"  This  interpretation  is  the  result  of  the  experiments 
of  Pachon  (of  Bordeaux)  and  his  pupil  Gachet  (1897). 
These  experiments  consisted  essentially  in  watching  the 
speed  of  digestion,  which  permitted  the  observers  to  note 
the  differences  between  the  activity  of  pancreatic  extracts 
from  animals  whose  spleen  had  been  removed,  and  nor- 
mal animals.  This  also  enables  them  to  state  with  cer- 
tainty the  activating  property  of  splenic  extract  from 
an  animal  while  digesting  on  pancreatic  digestion.  And 
these  authors  have  also  shown  that  the  splenic  substance 
endowed  with  such  properties  is  a  ferment.  This  was, 
therefore,  the  first  example  of  one  ferment  having  an 
activating  influence  on  another. 


96     THE  INTERNAL  SECRETIONS 

place;  and  a  third,  from  the  liver,  plays 
the  part  of  an  antibody. 

Thus  the  experiments  of  Herzen  and  of 
Lafayette  Mendel  and  Rettger  have  proven 
the  influence  of  the  blood  of  the  splenic  vein 
on  the  proteolytic  activity  of  the  pancreas. 

The  role  played  by  the  pancreas  as  a 
gland  of  internal  secretion  was  only  ap- 
preciated as  a  consequence  of  experiments 
on  extirpation  of  that  organ;  the  only  di- 
rect proof  was  furnished  by  experiments 
which  I  published  in  1891  showing  that  the 
ligature  of  all  the  pancreatic  veins  was 
followed  by  glycosuria.  But  these  experi- 
ments might  be  criticized  because  the  dogs 
operated  upon  survived  only  for  a  limited 
term.  The  experimental  grafting  of  the 
pancreas  (0.  Minkowski,  Hedon,  J.  Thiro- 
loix,  Gley  and  Thiroloix)  supplied  better 
demonstrations.  We  know,  however,  that 
Pfluger  contested  its  significance  in  the  last 
years  of  his  life.  Finally,  there  came  the 
experiments   of  uniting  two>  animals,   as 


CHARACTERISTICS  OF  GLANDS     97 

jointed  twins — parabiosis — made  by  J. 
For  setback  (1908-09).  Two  dogs  were  con- 
nected to  one  another,  the  pancreas  being 
removed  from  one  of  them.  It  was  found 
that  the  glycosuria  which  was  induced  in 
this  animal  remained  very  feeble  as  long  as 
it  was  in  symbiosis  with  the  other.  This  was 
evidently  because  the  substance  secreted 
by  the  pancreas  of  the  normal  dog,  and 
which  acted  on  the  assimilation  of  sugar, 
passed  into  the  blood  of  the  dog  without 
a  pancreas.  However,  it  had  first  passed 
through  the  blood  of  the  normal  animal 
and  was  thus  diluted ;  hence  the  slight  gly- 
cosuria. The  same  interpretation  applies 
to  the  laborious  experiments  that  Hedon 
has  carried  out  with  much  perseverance 
during  several  years.  Hedon  saw,  in  fact 
(1909-1912),  in  experiments  in  which  the 
circulations  of  diabetic  and  normal  dogs 
were  joined,  a  decided  diminution  of  gly- 
cosuria taking  place  within  several  hours 
following  the  mixture  of  the  blood  of  the 


98     THE  INTERNAL  SECRETIONS 

two  animals.  Furthermore,  he  has  stated  15 
that  the  transfusion  of  pancreatic  venous 
blood  into  the  general  circulation  of  a  dia- 
betic dog,  by  anastomosis  of  a  pancreatic 
vein  with  the  jugular  vein,  considerably 
reduces  the  excretion  of  sugar  in  the  de- 
pancreatized  animal;  and  he  has  found 
(1911)  that  when  venous  pancreatic  blood 
is  injected  into  the  mesenteric  vein  of  a 
diabetic  dog,  the  glycosuria  of  that  ani- 
mal diminishes  greatly  for  several  hours. 
It  is  thus  clear  that  the  metabolic  action 
of  the  pancreas  on  the  sugar  results  from 
an  internal  secretion. 

The  proof  of  the  anticoagulative  func- 
tion of  the  liver  which  was  given  by  Gley 
and  Pachon 16  has  been  completed  and  for- 

15  C.  B.  de  la  Soc.  Mol,  Feb.  1,  1913,  LXXIV,  238. 

"E.  Gley  and  V.  Pachon,  "Du  role  du  foie  dans 
Paction  anticoagulante  de  la  peptone"  (C.  B.  de  I' Acad, 
des  se.,  Aug.  26,  1895,  CXXI,  383);  "Influence  de 
1 'extirpation  du  foie  sur  1  'action  anticoagulante  de  la 
peptone"  (C.  B.  de  la  Soc.  de  Mol,  Nov.  23,  1895, 
XLVTI,  741) ;  cf.  also  Arch,  de  physiol.,  1895,  5th  series, 
VII,  711-717,  and  1896,  VIII,  715-723. 


CHARACTERISTICS  OF  GLANDS     99 

tified  by  the  experiments  of  Delezenne.17 
They  have  demonstrated  the  presence  in 
the  venous  hepatic  blood  of  the  anticoagu- 
lative  substance  which  one  can  force  the 
liver  to  produce  in  large  quantities  by  the 
administration  of  various  substances,  such 
as  albumoses,  extracts  of  various  organs, 
some  serums  and  venens,  etc. 

2.  In  the  case  of  the  two  hormones 
which  we  know  best — secretin  and  adrena- 
lin— proof  has  likewise  been  given  of  the 
passage  of  these  excitants  into  the  venous 
blood  of  the  organs  that  produce  them. 

The  experiments,  as  far  as  secretin  is 
concerned,  are  not  numerous,  but  we  may 
safely  consider  them  as   sufficient.     The 

17  C.  Delezenne,  ' '  Formation  d  'une  substance  anti- 
coagulante  par  circulation  artificielle  de  peptone  a 
travers  le  foie"  (Arch,  de  physiol.,  1895,  5th  series, 
VIII,  655-668);  "Kecherches  sur  le  mScanisme  de 
1 'action  anticoagulante  des  injections  intravasculaires  de 
peptone,  de  serum  d'anguille  et  d'extraits  d'organes" 
(in  Travaux  de  physiol.  du  labor atovre  du  professeur 
Hedon,  Montpellier  and  Paris,  1898,  pp.  212-262;  see 
page  241). 


100    THE  INTERNAL  SECRETIONS 

presence  of  this  excitant  in  the  venous 
blood  of  a  segment  of  the  jejunum  (Wert- 
heimer,  1903  ;18  Fleig,  1903 19)  and  even  in 
the  general  circulation  (carotid  blood,  En- 
riques  and  Hallion,  1903)  has  been  demon- 
strated. 

In  the  case  of  adrenalin  the  demonstra- 
tion is  as  perfect  as  is  possible.  Small 
doses  of  venous  suprarenal  blood  manifest 
all  the  properties  of  suprarenal  extract  by 
their  action  on  the  sympathetic  system  and, 
furthermore,  their  action  is  indeed  that  of 
adrenalin  itself.20  According  to  my  experi- 
ments, it  is  sufficient  to  inject  1  cc.  in  a 
kilogram  weight  of  the  animal,  or  even 
less — 0.7  cc.  in  some  cases — into  a  dog  to 

18  It  should  be  remarked,  however,  that  Wertheimer's 
experiments  were  not  carried  out  with  the  normal  ex- 
citant of  the  duodenojejunal  mucous  membrane — hydro- 
chloric acid — which  liberates  the  secretin  of  this  mucosa, 
but  with  essence  of  mustard  and  with  ether. 

19  Fleig 's  experiments  were  made  with  the  use  of  hy- 
drochloric acid  as  the  excitant  of  the  mucous  membrane. 

20 1  do  not  think,  however,  that  any  one  has  as  yet  en- 
deavored to  produce  adrenalinic  glycosuria  by  the  injec- 
tion of  suprarenal  venous  blood. 


CHABACTEBISTICS  OF  GLANDS   101 

provoke  a  very  pronounced  cardiovascular 
reaction. 

As  for  the  mammary  hormone,  the  pres- 
ence in  the  blood  of  a  substance  exciting 
the  secretion  of  milk  has  only  been  proven 
indirectly.  First,  by  the  experiments  of 
MironorY,21  which  showed  that  after  the 
section  of  all  the  nerves  of  the  mammary 
gland  in  the  she-goat,  the  breasts  were 
nevertheless  hypertrophied  after  the  young 
had  been  brought  forth ;  they  secreted  like 
those  of  a  normal  animal.  This  fact  was 
confirmed  by  the  experiments  of  Eibbert 
(1897-98),  which  consisted  in  the  trans- 
plantation of  mammary  gland  tissue  under 
the  skin  of  the  auricle  of  a  female  guinea- 
pig.  The  transplant  took,  developed  and 
even  secreted  when  the  guinea-pigs  were 
impregnated.22    And  it  is  also  confirmed 

21 M.  Mironofp,  ' '  De  1  'influence  du  systeme  nerveux 
sur  le  fonctionnement  des  glandes  mammaires ' '  (Arch, 
des  sc.  biol.,  1895,  III,  353-380). 

23  These  experiments  have  been  successfully  repeated 
on  the  bitch  by  K.  Basch  (Deutsche  med.  Woch.,  May 
26,  1910). 


102    THE  INTERNAL  SECRETIONS 

by  observations  on  the  Czech  pygopagus 
monster, — the  two  connected  sisters,  Rosa 
and  Josepha  Blazek.  When,  three  years 
ago,  one  of  them,  Rosa,  became  pregnant, 
twelve  days  after  she  had  been  confined  the 
breasts  of  her  sister  Josepha  were  enlarged 
like  hers  and  secreted  milk  at  least  as  well 
as  those  of  Rosa.23 

The  origin  of  this  substance  that  excites 
the  secretion  of  milk — the  galactogogue 
hormone — has  not  as  yet  been  absolutely 
determined.  It  may  come  from  the  plaL 
centa  (K.  Basch,  1909;  B.  Aschner  and  Ch. 
Grigoriu,  1911),  or  from  the  myometrial 
glands  of  the  uterus  (Ancel  and  Bouin, 
1911),  or  from  the  suppression  of  an  in- 
hibitory stimulus  of  fetal  origin,  since  al- 
though the  development  of  the  gland  takes 
place  during  pregnancy,  its  secretion  is 
not  established  till  after  the  close  of  the 
gravid  period,  when  the  fetus  is  expelled. 

88  C.  Teunecek,  ' '  L  'accouchement  du  pygopage  Rosa- 
Josepha  Blazek"  (Semaine  m6d.,  May  18,  1910,  p.  229). 


CHARACTERISTICS  OF  GLANDS   103 

This  is  the  theory  of  Lane-Claypon  and 
Starling.24  In  this  uncertainty  it  would 
evidently  be  desirable  that  some  one  should 
discover  in  the  venous  blood  of  some  organ 
the  hormone  which  acts  on  the  mammary 
gland.25 

That  the  waste  products  should  play  the 
part  of  excitants,  they  must  be  found  in 
the  venous  blood  of  the  organ  which  pro- 
duces them.     This  appears  to  be  the  case 

34  The  experiments  of  Lane-Claypon  and  Starling  have 
not  been  confirmed  in  all  points  by  C.  Foa  (Arch,  di 
fisiologia,  1908,  V,  520-532).  The  latter,  moreover,  sets 
the  important  question,  Does  the  mammary  gland,  once 
it  is  developed,  have  need  of  a  functional  stimulant  and 
does  not  the  supply  of  materials  necessary  for  the  forma- 
tion of  milk  -which  is  brought  by  the  blood  suffice  to 
establish  and  maintain  the  secretion? 

36  E.  A.  Schafee  has  recently  announced  (XYIIth 
Intern.  Congress  of  Medicine,  London,  1913,  section  II, 
Physiology,  Part  II,  p.  81)  that  the  serum  of  normal 
animals — e.g.,  guinea-pigs — may  at  times  have  a  galac- 
tagogue  action  on  the  cat  in  lactation;  but  he  was  not 
able  to  determine  the  conditions  which  make  this  prop- 
erty appear.  Some,  however,  he  adds,  may  be  disposed 
to  think  that  this  " galactagogue  hormone"  comes  from 
the  posterior  lobe  of  the  hypophysis.  For  the  moment, 
however,  this  is  only  an  hypothesis. 


104    THE  INTERNAL  SECRETIONS 

with  urea  at  least  (experiments  of  E.  de 
Cyon,  1870;  W.  von  Schroder,  1882,  etc.). 
But  does  the  urea  of  the  blood,  upon  arriv- 
ing at  the  kidneys  where  it  is  eliminated, 
become  an  excitant  of  the  renal  cells  1  We 
know  nothing  which  permits  us  to  affirm 
this,  although  the  diuretic  action  of  urea, 
when  injected  in  quite  strong  doses,  is  well 
established. 

Carbon  dioxid,  as  is  well  known,  is 
found  not  only  in  the  blood  of  any  particu- 
lar organ,  but  in  the  blood  of  all  organs. 
This  is  (see  below)  one  of  the  reasons  why 
we  (Gley,  Meltzer)  do  not  consider  this 
substance  as  a  true  hormone. 

It  is  now  to  be  remarked  that  none  of  the 
internal  secretory  products  with  a  morpho- 
genic  action — this  term  will  be  defined  later 
on — has  been  found  in  the  venous  blood 
of  the  glands  in  which  we  have,  on  some 
other  grounds,  reasons  for  admitting  their 
existence.  The  physiological  attempts  made 
with  thyroid  blood,  as  I  have  already  ob- 


CHARACTERISTICS  OF  GLANDS  105 

served,  have  up  to  now  been  fruitless.  No 
one  has  ever,  for  anatomical  reasons,  at- 
tempted to  collect  the  blood  which  comes 
from  the  hypophysis,  ovaries  or  thymus. 
It  should  be  possible  to  make  this  attempt 
with  the  testicle;  and  it  is  much  to  be  de- 
sired that  this  be  done. 

Definitely  speaking,  the  sum  total  of  our 
knowledge  of  the  properties  of  the  various 
sorts  of  glandular  venous  blood  is  very 
modest.  While  the  doctrine  of  internal  se- 
cretions has  been  expanding  more  and 
more,  the  solid  foundation  on  which  it  rests 
has  remained  narrow,  for  the  substances 
whose  presence  in  the  venous  blood  has 
been  physiologically  demonstrated  in  an 
indisputable  manner  number  only  four :  the 
pancreatic  substance  which  serves  to  regu- 
late the  normal  glycemia,  the  hepatic  anti- 
thrombine,  secretin  and  adrenalin. 

Action  of  Organic  Extracts. — Besides 
the  methods  of  study  of  the  products  of 
internal  secretion  mentioned  above,  there 


106    THE  INTERNAL  SECRETIONS 

is  another  and  more  simple  one ;  in  fact  so 
simple  that  it  has  turned  experimenters 
from  the  rational  path,  which  is  the  inves- 
tigation of  the  physiological  properties  of 
venous  blood  from  various  sources.  The 
other  method  consists  in  the  administration 
of  organic  extracts. 

It  is  but  just  to  recognize  that  there  was, 
besides  its  ease,  a  scientific  excuse  for  the 
use  of  this  method  which  has  spread  so 
widely  and  rapidly.  The  first  extracts  to 
be  thus  studied  successfully  were  from  the 
thyroid  and  suprarenal  bodies.  Thyroid 
extract  manifested,  even  in  the  first  experi- 
ments (Gr.  Vassale,  Gley)  and  the  first  ap- 
plications to  the  treatment  of  myxedema 
(G.  R.  Murray),  its  specific  action  against 
disorders  arising  from  the  suppression  of 
the  thyroid  secretion.  From  this  it  was  to 
be  seen  that  the  injection  of  an  organic  ex- 
tract replaces  immediately  and  for  the  time 
being  the  function  of  that  organ.  This  led 
to  attempts  to  generalize  and  to  use  ex- 


CHARACTEEISTICS  OF  GLANDS  107 

tracts  from  other  organs  in  the  same  man- 
ner. The  unfortunate  experiences,  for  ex- 
ample, in  the  treatment  of  Addison's  dis- 
ease by  suprarenal  medication,  or  in  the 
employment  of  pancreatic  extracts  against 
diabetes,  did  not  stop  these  therapeutic  at- 
tempts. Besides,  the  important  discovery 
by  Oliver  and  Schafer  of  the  cardiovascu- 
lar action  of  suprarenal  extract,  confirmed 
a  year  later  by  the  discovery  of  the  similar 
action  of  the  suprarenal  blood,  appeared  to 
show  the  excellence  of  this  method  and  it 
paved  the  way  for  the  discovery  of  the 
specific  properties  of  internal  secretions. 
The  result  is  that  nearly  all  the  investiga- 
tions made  in  the  past  fifteen  years  on  this 
question  have  followed  a  method  which, 
while  not  absolutely  defective,  is  incom- 
plete and  therefore  inadequate. 

Not  that  several  warnings  have  not  been 
given.    "It  is  necessary,"  I  said  in  1899,26 

'•In  Ch.  Bouchard's  "Trait6  de  pathologie  g6n.,"  t. 
Ill,  p.  169. 


108    THE  INTERNAL  SECRETIONS 

"to  ask  oneself  if  all  the  glands  in  ques- 
tion .  .  .  normally  produce  substances 
identical  with  those  whose  actions  are  man- 
ifested by  their  extracts.  In  fact,  the  sub- 
stances contained  in  the  extracts  may  not 
exist  in  the  living  glandular  tissue;  fur- 
thermore, nothing  proves  a  priori  that,  if 
they  are  formed  in  the  living  gland,  they 
regularly  leave  it  by  the  blood  vessels  in 
order  to  exercise  their  influence  on  the  dif- 
ferent arterial  regions  of  the  organism. 
...  It  is  necessary  that  the  demonstration 
given  for  the  suprarenal  bodies  be  also 
supplied  for  the  other  glands.  .  .  .  This 
demonstration  is  particularly  necessary, 
for  example,  in  the  case  of  the  thyroid 
gland." 

In  the  same  year  Lewandowsky 27  re- 
marked in  connection  with  the  suprarenal 
extract,  that  we  cannot  conclude  anything 
about  the  action  of  an  organ  in  the  body 
from  the  results  of  injecting  an  extract  of 

"Ztschr.  f<iir  Min.  Med.,  XXXVII,  535-46. 


CHARACTERISTICS  OF  GLANDS  109 

that  organ  into  the  blood.  M.  Lambert,28 
in  giving  his  first  warning  of  the  toxicity 
of  extracts  of  the  corpora  lutea,  adds:  "I 
will  take  good  care  not  to  formulate  an 
hypothesis  on  the  mechanism  of  internal 
secretion  of  the  corpus  luteum  because  of 
these  observations.  The  activity  or  the  tox- 
icity of  any  organ  whatsoever  does  not  au- 
thorize such  deductions.  The  isolation  of 
substances,  elsewhere  so  interesting,  ex- 
tracted from  those  glands  of  internal  se- 
cretion which  have  been  most  studied,  has 
not  yet  led  to  any  sure  conclusions  as  to 
the  role  they  play  in  the  economy. ' '  Later, 
Biedl  expressed  himself  as  of  the  same 
opinion : 29  "To  prove  conclusively  that 
in  an  organic  extract  we  have  a  hormone, 
the  product  of  internal  secretory  activity 
of  the  particular  organ  we  deal  with,  we 
must  first  establish  two  postulates,  in  ef- 
fecting which,  at  the  present  state  of  our 

28  C.  B.  de  la  Soc.  de  biol,  Jan.  12,  1907,  p.  18. 
29"Innere  Sekretion,"  2nd  Ed.,  vol.  i,  p.  30. 


110    THE  INTERNAL  SECRETIONS 

knowledge,  we  encounter  great  difficulties. 
First,  it  is  absolutely  necessary  that  we 
have  a  thorough  knowledge  of  the  chemis- 
try of  the  active  substance.  In  this  direc- 
tion there  is,  as  yet,  a  vast  field  for  re- 
search before  us.  ...  A  second,  just  as 
important,  postulate  lies  in  the  proof  that 
the  active  substance  shown  to  be  present 
in  the  organic  extract  is  produced  in  the 
gland  intra  vitam  and  is  discharged  into 
the  circulating  blood."  And  Biedl  shows 
that  the  only  hormone  which  responds  to 
these  two  desiderata  is  adrenalin. 

No  attention  has  been  paid  to  these 
warnings.  It  is  therefore  of  importance 
to  recall  that  from  the  action  of  an  or- 
ganic extract  we  have  no  right  to  draw  con- 
clusions as  to  its  internal  secretion  with- 
out further  investigation,  as  has  been  done 
only  too  often.  In  order  to  admit  that  an 
organ  has  such  a  function,  we  must,  at  least 
in  the  absence  of  the  above  mentioned 
chemical  and  physiological  requirements — 


CHARACTERISTICS  OF  GLANDS  111 

discovery  of  a  specific  product  in  the  ve- 
nous blood — have  a  mass  of  concordant 
facts,  of  physiological,  pathological  and 
therapeutic  nature.  It  is  necessary  that 
the  extirpation  of  the  organ  to  which  we 
attribute  an  internal  secretion  give  rise  to 
a  series  of  functional  disorders,  to  a  syn- 
drome (which  may  attain  actual  disease  in 
man)  the  attenuation  or  eradication  of 
which  is  obtained  through  the  administra- 
tion of  an  extract  of  the  organ,  or  through 
grafting  whenever  the  latter  is  possible. 
The  success  of  this  substitution  therapy  is 
the  counterproof  of  experiments  consisting 
in  the  destruction  of  organs.  It  is  because 
this  concordant  mass  of  facts  has  been  ob- 
tained in  the  study  of  the  function  of  the 
thyroid  and  in  that  of  the  interstitial 
glands  of  the  germinal  organs  that  the  thy- 
roid, the  interstitial  testicular  gland  and 
the  corpus  luteum  are  justly  considered  as 
organs  of  internal  secretion. 

The  determination  of  the  action  of  or- 


112    THE  INTERNAL  SECRETIONS 

ganic  extracts,  taken  by  itself,  is  power- 
less to  reveal  such  a  function. 

Not  that  I  fail  to  realize  the  importance 
of  some  of  the  results  that  have  been  at- 
tained through  investigations  of  organic 
extracts.  And  when  I  think  of  the  infor- 
mation on  the  physiological  action  of  vari- 
ous extracts  that  has  been  furnished  us 
through  such  studies,  from  which  interest- 
ing therapeutic  applications  have  resulted; 
when  I  think  of  the  contributions  supplied 
to  the  question  of  the  coagulation  of  the 
blood,  of  theories  of  immunity,  etc.,  I  am 
almost  tempted  to  regret  my  criticisms. 
For  I  would  not  like  to  appear  ungrateful 
towards  so  many  assiduous  investigators. 
But  the  physiologist,  seeing  matters  from 
his  own  particular  point  of  view,  must 
maintain  his  criticisms.  We  will  soon  see 
how  important  these  are,  especially  at 
present.  Besides,  it  is  less  a  question  of 
combating  this  method  of  investigation 
itself  than  of  stopping  its  almost  exclusive 


CHARACTERISTICS  OF  GLANDS   113 

use  and  the  abuses  which  it  has  suffered  in 
the  investigation  of  internal  secretions.  It 
has  held  back  work  on  the  physiological 
properties  of  venous  blood  coming  from 
the  various  organs.  To  be  sure,  the  latter 
method  is  much  more  laborious,  infinitely 
more  difficult  and  less  fertile  in  immediate 
results,  but  it  is  surer  and  more  precise. 

The  study  of  internal  secretions  by  the 
method  of  administration  of  organic  ex- 
tracts raises  objections  of  principle,  or  the- 
oretical objections,  and  objections  of  fact. 

1.     Theoretical  Objections: 

A.  There  is  no  available  a  priori  proof 
that  the  substances  present  in  the  extract 
existed  in  the  living  glandular  tissue. 

B.  There  is  no  proof  that  the  sub- 
stances present  in  the  living  gland  are 
regularly  excreted  into  the  venous  blood 
of  the  gland. 

C.  Every  extract  of  an  organ  is  a  con- 
glomeration of  substances,  and  this  con- 


114    THE  INTERNAL  SECRETIONS 

glomeration  is  evidently  not  discharged  at 
random,  or  continuously,  into  the  venous 
blood  of  the  organ.  On  the  contrary,  ac- 
cording to  what  we  know,  it  would  seem 
that  when  required  for  special  physiologi- 
cal purposes  at  a  given  moment,  a  certain 
substance  passes  in  the  venous  blood,  a 
sole  product  of  secretion. 

D.  Likewise,  the  physiological  action  of 
an  organic  extract,  which  contains  various 
substances,  can  only  be  complex;  nothing 
proves  that  the  venous  blood  of  the  organ 
has  this  action. 

To  sum  up,  organic  extracts,  no  matter 
what  is  their  origin  and  mode  of  prepara- 
tion, surely  contain  substances  other  than 
the  products  which  the  living  organ  de- 
livers to  the  venous  blood.  What  are  the 
physiological  and  toxicological  actions  of 
these  substances,  and  how  are  we  to  recog- 
nize those  of  the  specific  products?  May 
not  the  properties  of  the  one  mask  or  ex- 
aggerate those  of  the  other,  and  to  what 


CHARACTERISTICS  OF  GLANDS   115 

degree  is  this  a  fact?  These  questions 
cannot  be  answered  at  the  present  state  of 
our  knowledge. 

2.  Objections  of  Fact. — Then  come  the 
objections  of  fact,  of  which  there  are  many. 
First,  there  is  to  be  considered  the  well- 
known  toxicity  of  organic  extracts,  per  se, 
which  may  mask  the  action  of  the  specific 
products. 

Furthermore,  as  this  toxicity  is  very 
variable — changing  according  to  the  ori- 
gin,30 the  mode  of  preparation,  the  time 

30  Numerous  examples  of  this  fact  could  be  mentioned. 
I  will  only  cite  Peakce's  experiments  with  kidney  ex- 
tracts (quoted  by  J.  L.  and  E.  M.  Miller,  "The  Effect 
on  Blood  Pressure  of  Organ  Extracts,"  J.  of  Physiol., 
1911,  XLIII,  pp.  242-246)  and  those  of  Champy  and 
Gley  with  extracts  of  corpus  luteum  (Soc.  de  biol.,  July 
22,  1911,  p.  159).  It  is  of  interest  to  note  here  that 
the  action  of  organic  extracts  may  vary  according  to 
conditions  of  the  animal  from  which  they  were  derived 
(sex,  age,  inanition,  fatigue,  sexual  activity,  etc.)  ;  cf. 
Aldo  Patta,  "Contributo  critico  e  sperimentale  alio 
studio  dell'azione  degli  estratti  di  organi  sulla  funzione 
circolatoria "  (Archivio  fi  farmacologia  sperimentale  e 
sciense  aflini,  1906,  V,  pp.  188-215  and  576-605,  and 
1907,  VI,  80-119). 


116    THE  INTERNAL  SECRETIONS 

that  has  elapsed  between  the  extirpation 
of  the  organ  and  the  preparation  of  the 
extracts,  the  degree  of  autolysis  that  could 
have  taken  place  in  the  interval,  the  site  of 
administration,  the  method  of  use  (dilu- 
tion, heat,  speed  of  absorption),  the  man- 
ner in  which  the  organ  was  preserved,31 
etc. — we  may  ask  ourselves  if,  in  the  midst 
of  such  variations — depending  on  so  many 
complex  and  variable  factors,  some  of 
which  are  difficult  and  others  impossible  to 
control — the  action  of  a  specific  principle 
is  assured  and  constant.  At  least  it  would 
be  necessary  that  proof  of  this  identity 
and  constancy  be  given.  And  it  is  certain 
that  experimenters  do  not  always  guard 

31 1  have  shown  that  organic  extracts,  even  though 
preserved  in  aseptically  prepared  powders  and  carefully 
dried,  quickly  lose  their  toxicity  (E.  Gley,  "Toxicite 
des  extraits  d'organes,  tachyphylaxie,  anaphylaxie, ' '  in 
Melanges  biologiques,  Jubilee  volume  of  Prof.  Ch.  Eichet, 
Paris,  1912,  pp.  111-129).  This  simple  observation  ex- 
plains both  the  uncertainty  of  the  method  of  organic 
extracts  and  why  they  may  prove  themselves  untrust- 
worthy in  many  therapeutic  attempts. 


CHARACTERISTICS  OF  GLANDS   117 

against  all  these  difficulties.  Undoubtedly, 
a  considerable  part  of  the  contradictions 
that  may  be  noted  in  the  reports  of  experi- 
mental investigations  is  due  to  this  cause. 

The  multiplicity  of  organic  extracts 
which  provoke  an  identical  physiological 
reaction  is  proof  of  the  non-specificity  of 
these  extracts  and  shows  that  we  have  to 
do  here  with  a  more  or  less  general  phar- 
macodynamic effect.  It  is  for  this  reason 
that  a  galactagogue  action  has  been  attrib- 
uted by  Schaf er  and  Mackenzie  32  to  ex- 
tracts of  the  hypophysis,  corpora  lutea, 
uterus  (in  evolution),  mammary  glands 
(during  lactation)  and  by  Isaac  Ott  and  J. 
C.  Scott 33  to  the  same  pituitary  and  cor- 

aaE.  A.  Schafer  and  K.  Mackenzie,  "The  Action  of 
Animal  Extracts  on  Milk  Secretion"  (Proceedings  of 
the  Eoyal  Soc,  1911,  LXXXIV,  Series  B,  p.  16) ;  K. 
Mackenzie,  "An  Experimental  Investigation  of  the 
Mechanism  of  Milk  Secretion,  with  Special  Eeference  to 
the  Action  of  Animal  Extracts"  (Quarterly  Jour,  of 
Experimental  Physiol,  1911,  IV,  305-336). 

M  I.  Ott  and  J.  C.  Scott,  ' <  The  Action  of  Animal  Ex- 
tracts upon  the  Secretion  of  the  Mammary  Gland" 
(Therapeutic   Gas.,   Oct.,   1911);    "Action  of  Different 


118    THE  INTERNAL  SECRETIONS 

pora  lutea  extracts,  and  besides  to  extracts 
of  the  thymus  and  the  pineal  gland.34  It  is 
thus  that  extracts  of  the  thymus,  the  thy- 
roid, testicles,  prostate,  and  pancreas  pro- 
voke contraction  of  the  bladder.35  From 
these  two  examples  alone  we  can  see  that 
extracts  of  the  most  divers  organs,  organs 
which  play  no  part  in  the  system  to  which 
the  stimulated  organ  belongs,  as  well  as 
organs  dependent  on  the  same  apparatus, 
start  either  a  secretion  or  a  contraction  of 
a  smooth  muscle.  Is  it  not  plausible  that 
this  action  depends  on  the  presence  of  a 
substance  which  occurs  in  all  these  ex- 
tracts, consequently  a  substance  that  is 
quite    widely    distributed,    and   therefore 

Agents  upon  the  Secretion  of  Milk"  (Ibid.,  May,  1912, 
p.  310);  "The  Action  of  the  Internal  Secretions  upon 
the  Milk  Secretion"  (Ibid.,  November,  1912,  p.  761). 

M  Pituitary  extract  and  that  of  corpora  lutea  have 
been  shown  to  be  inactive  in  a  therapeutic  attempt  on 
a  woman  and  in  several  experiments  on  milch  cows. 

33 1.  Ott  and  J.  C.  Scott,  "The  Action  of  Animal  Ex- 
tracts upon  the  Bladder"  (Monthly  Cyclopedia  and 
Medical  Bull.,  July,  1911). 


CHARACTERISTICS  OF  GLANDS    119 

rather  general  than  specific?  And  would 
it  not  be  opportune  to  investigate  whether 
the  venous  blood  of  some  one  of  these  or- 
gans does  not  manifest,  either  on  the  blad- 
der or  on  the  female  breasts,  the  action 
stated  to  occur  when  organic  extracts  are 
used? 

It  may  be,  moreover,  that  the  adminis- 
tration of  organic  extracts  is  followed  by 
anaphylactic  reactions,  since  these  extracts 
contain  foreign  albumins.  This  observa- 
tion applies,  above  all,  to  the  therapeutic 
use  of  many  of  them,  inasmuch  as  atten- 
tion has  been  called  elsewhere  in  this  book 
to  the  consecutive  anaphylactic  phenomena 
following  the  injection  of  protein  sub- 
stances. 

The  phenomena  of  tachyphylaxia,  or 
very  rapid  immunization  against  the  toxic 
action  of  an  organic  extract,  upon  which 
light  was  shed  by  the  researches  of  Cesa- 
Bianchi  in  Italy,  H.  Dold  in  Germany,  An- 


120    THE  INTERNAL  SECEETIONS 

eel,  Bourn  and  Lambert,  and  Champy  and 
Gley  3e  in  France,  shows  how  very  impru- 
dent it  is  to  consider  an  extract  against 
which  the  organism  protects  itself  in  sev- 
eral minutes  as  a  product  of  internal  se- 
cretion. The  phenomenon  of  tachyphy- 
laxia  for  a  given  extract  may  be  provoked 
by  another  extract,  and  vice  versa,  as  was 
shown  by  Cesa-Bianchi,  Ancel,  Bouin  and 
Lambert,  and  Champy  and  Gley.  It  is 
what  the  latter  have  termed  crossed  tachy- 
phylaxia,  and  herein  lies  an  important  fact, 
which,  in  the  face  of  actual  therapeutic  at- 
tempts at  simultaneous  or  successive  ad- 
ministration of  several  extracts,  should  not 
be  forgotten. 

Most  certainly,  the  question  is,  above  all, 

38  The  bibliography  of  this  question  is  to  be  found 
in  Cesa-Bianchi 's  memoir:  "  Contribute  alia  conso- 
scenza  de  meeanismo  di  azioni  degli  estratti  polmonari ' ' 
(Archivio  di  farmacol.  sperimentale  e  sciensi  affini,  1912, 
XIII,  pp.  407-453,  481-514,  and  529-546),  and  in  a  work 
by  Gley:  "Les  phenomenes  de  tachyphylaxie  et  leur 
signification  prSsente"  (Arxivs  de  I'lnstitut  de  ciencies, 
I,  No.  2,  Barcelona,  1912). 


CHARACTERISTICS  OF  GLANDS    121 

to  learn  if  there  is  tachyphylaxia  against 
the  specific  action  as  well  as  against  the 
general  toxic  action  of  organic  extracts. 
In  fact,  the  phenomenon  may  be  a  means  of 
defense  against  this  toxic  action  and  not  be 
produced  in  the  presence  of  specific  ac- 
tions. "The  work  to  be  undertaken  at 
present  is  therefore  the  careful  investiga- 
tion of  the  individual  actions  which  the  va- 
rious organic  extracts  may  have,  indepen- 
dent of  their  general  toxic  action,  which 
we  now  know  to  be  accompanied  by  this 
tachyphylactic  reaction.  .  .  .  Many  phy- 
sicians and  several  physiologists  tend  to 
accord  to  organic  extracts,  considered  as 
substitutes  for  internal  secretions,  great 
importance  in  the  regulation  of  arterial 
pressure.  Does  it  not  appear  that  all  stud- 
ies made  in  this  direction  must  be  reversed 
in  the  light  of  the  new  notion  of  tachy- 
phylaxia? And,  likewise,  other  effects 
hitherto  attributed  to  the  action  of  various 


122    THE  INTEBNAL  SECEETIONS 

organic  extracts  must  be  traced  back  to 
this  phenomenon. ' ' 37 

Now,  Howell 38  has  already  noticed  that 
a  second  injection  of  pituitary  extract,  ad- 
ministered soon  after  the  first,  has  not  the 
same  effect  on  the  arterial  pressure  as  the 
first,  which  fact  was  verified  by  Schafer 
and  Swale  Vincent.39  Later,  iStienne  and 
J.  Parisot 40  found  that  repeated  injections 
of  the  same  extract  no  longer  provoked 
the  augmentation  of  the  force  of  the  car- 

37  E.  Gley,  loc.  cit.;  Arxivs  de  I'Institut  de  ciencies,  I, 
p.  21. 

38 W.  H.  Howell,  "The  Physiol.  Effect  of  Extracts  of 
Pituitary  Body"  (Jour,  of  Exper.  Med.,  1898,  III,  215, 
245). 

38 E.  A.  Schafer  and  Swale  Vincent,  "On  the  Ac- 
tion of  Extract  of  Pituitary  Injected  Intravenously" 
( Jour,  of  Physiol.,  1899,  XXIV,  p.  xix) ;  "The  Physiol. 
Effects  of  Extracts  of  Pituitary,"  Ibid.,  1899,  XXV,  p. 
87-97).  The  authors  even  take  care  to  remark  that  this 
particular  differentiates  the  action  of  pituitary  extract 
from  that  of  suprarenal  extract. 

*°  G.  ifDTiENNE  and  J.  Parisot,  ' '  Action  sur  1  'appareil 
cardio-vasculaire  des  injections  repetees  d'extrait  d'hy- 
pophyse.  Comparison  avec  1 'action  de  1 'adrenaline " 
(Arch,  de  med.  exper.  et  d'anat.  pathol.,  1908,  XV,  pp. 
423-437). 


CHARACTERISTICS  OF  GLANDS    123 

diac  pulsations  which  was  caused  by  the 
first  injection;  and  J.  Salvioli  and  A.  Car- 
raro  41  have  affirmed  the  same  fact.  Have 
we  here  to  deal  with  another  action  of  the 
same  extract?  We  again  find  the  same 
particular  circumstances:  v.  Frankl-Hoch- 
wart  and  A.  Frohlich  42  have  observed  that 
the  action  of  successive  injections  of  pitui- 
tary extract  on  the  bladder  is  less  and  less 
marked ;  and  E.  A.  Schafer  and  P.  T.  Her- 
ring 43  remarked  that  a  second  injection 
is  less  sure  than  the  first  to  cause  dilata- 
tion of  the  renal  vessels  and  diuresis. 
Furthermore,   Roger   and   Josue 44   found 

**  J.  Salvioli  and  A.  Carraro,  ' '  Sur  la  physiologie 
de  l'hypophyse"  (Arch,  italiennes  de  biologie,  1908, 
LXIX,  pp.  1-38). 

43  V.  Frankl-Hochwart  and  Frohlich,  "tJber  die 
Wirkung  des  Pituitrins"   (Wiener  hlin.   Wschr.,  1909). 

*" E.  A.  Schafer  and  P.  T.  Herring,  "The  Action  of 
Pituitary  Extracts  upon  the  Kidney"  (Proceedings  of 
the  Boyal  Soc,  1906,  LXXI,  p.  571).  The  diuretic  ac- 
tion of  pituitary  extract  was  discovered  by  E.  A. 
Schafer  and  R.  Magnus  (Proc.  of  the  Boyal  Soc.,  July 
20,  1901;  J.  of  Physiol,  XXVII). 

"H.  Eoger  and  O.  Josue,  "Action  de  l'extrait  d'in- 


124    THE  INTERNAL  SECRETIONS 

that  the  fall  of  arterial  pressure  caused  by 
the  injection  of  intestinal  extract  (aqueous 
extract  of  frozen,  macerated  rabbit's  in- 
testine) was  not  reproduced  by  a  second 
injection.  Together  with  Champy,  I  have 
demonstrated  the  same  fact  in  the  case  of 
extract  of  corpora  lutea.  From  this  we 
concluded  that  it  is  difficult  to  admit  the 
assumption  of  a  normal  vaso-dilatatory 
action  exercised  by  the  secretory  products 
of  the  corpora  lutea. 

Such  experiments  should  be  methodi- 
cally pursued  with  the  extracts  of  organs 
ordinarily  used.  These  researches  are  all 
the  more  imperative  now  that  we  have 
learned  to  recognize  the  difference,  with 
regard  to  the  tachyphylactic  reaction,  be- 
tween suprarenal  extract,  which  deter- 
mines this  reaction  (Cesa-Bianchi),  and 
the  active  principle  of  this  extract,  adren- 
alin, which  does  not  provoke  it  (see  p.  158). 

testin  sur  la  pression  arterielle"  (C.  B.  de  la  Soc.  de 
biol,  Feb.  24,  1906,  LVIII,  p.  371). 


CHARACTERISTICS  OF  GLANDS   125 

We  know,  for  example,  that  several  suc- 
cessive injections  of  adrenalin  may  be 
given  without  missing  the  hypertensive  ef- 
fects after  any  of  them.  Does  the  organ- 
ism have  the  same  tolerance  for  other  ac- 
tions of  adrenalin?  Does  not  the  ques- 
tion confront  us  since  the  experiments 
of  N.  Waterman  (1911),  which  tend  to 
show  that  a  sort  of  immunization  may  be 
produced  against  glycosuria  resulting 
from  the  administration  of  adrenalin? 
Moreover,  we  must  not  be  at  all  surprised 
at  this,  for  we  know  that  the  hypertensive 
action  of  adrenalin  and  its  property  of  ac- 
cumulating sugar  go  on  pari  passu,  accord- 
ing to  the  researches  of  P.  Hari.45  We  can 
see  how  complex  may  be  at  times  the  in- 
vestigation of  the  phenomenon  of  tachy- 
phylaxia,  the  question  of  learning  if  a  cer- 
tain active  principle  of  an  organic  extract 

45  Paul  Hari,  "  Tiber  den  Einflus  des  Adrenalins  auf 
den  Gaswechsel"  (Biochem.  Ztschr.,  1912,  XXXVIII, 
23-45). 


126    THE  INTERNAL  SECRETIONS 

gives  rise  to  a  tachyphylactic  reaction,  as 
does  the  entire  extract. 

The  facts  of  tachyphylaxia,  taken  all  in 
all,  form  a  very  strong  argument  against 
the  significance,  too  easily  accorded,  of  the 
pharmacodynamic  action  of  organic  ex- 
tracts. For  it  is  one  of  the  characteristics 
of  an  internal  secretion  that  its  effects  can 
be  repeated  quasi-indefinitely.  Adrenalin 
and  secretin  behave  thus.  Can  we,  on  the 
contrary,  see  a  product  of  internal  secre- 
tion in  an  extract  against  the  effects  of 
which  a  protective  reaction — tachyphy- 
laxia— is  established  so  rapidly — no  mat- 
ter what  else  might  be  the  mechanism  of 
this  reaction?  Or,  if  there  is  really  an 
internal  secretion  in  the  extract,  should 
we  not  think  that  its  specific  action  may  be 
masked  by  the  toxic  action  of  the  complex 
substances  composing  the  extract  as  soon 
as  a  stage  is  reached  when  a  defensive 
reaction  of  the  organism  manifests  itself? 

Finally,  there  is  another  objection  which 


CHARACTERISTICS  OF  GLANDS  127 

is  no  less  important.  It  arises  from  a  fact 
to  which,  it  would  seem,  little  attention 
has  been  accorded.  There  are  extracts 
with  which  a  characteristic  physiological 
effect  can  be  obtained  only  by  injections 
of  large  doses,  and  these  doses  are  often  so 
excessive  that  they  represent  in  weight 
the  total  mass  of  the  organs  from  which 
these  extracts  were  obtained,  and  even 
several  of  these  organs.  A.  Patta,46  for 
example,  has  stated  this  to  be  the  case 
when  extracts  of  thyroid,  thymus,  hypoph- 
ysis, ovaries  or  testicles  act  on  the  cir- 
culation: "per  otteneri  fenomeni  apprez- 
zabili,"  he  says,  "spesso  occorsero  dosi 
de  estratto  corrispondenti  a  parecchi  or- 
gani."  This  is  a  fact  which  I  have  often 
had  occasion  to  observe  with  thyroid  ex- 
tract and  which  was  also  noticed  by  Quin- 
quaud  and  myself  in  our  researches  on  the 

"Aldo  Patta,  "Contributo  critico  e  sperimentali  alio 
studio  dell'azione  degli  estratti  di  organi  nella  funzioni 
circulatoria "   (loc.  tit.,  VI,  1907;  see  above  p.  115). 


128    THE  INTERNAL  SECRETIONS 

influence  of  organic  extracts  on  the  supra- 
renal secretion.47 

Taken  by  themselves,  these  two  facts — 
tachyphylaxia  and  the  activity  of  extracts 
in  extra-physiological  doses — suffice  to 
throw  suspicion  on  the  therapeutic  method 
of  organic  extracts,  in  the  manner  that  it 
has  been  and  still  is  commonly  applied. 

It  is  not,  therefore,  astonishing  that  the 
exclusive  use  of  this  method  has  led  to 
many  unjustified  conclusions;  too  many 
risky  theories  have  been  propounded;  too 
many  hazardous  applications  have  been 
made.  Not  that  there  is  a  question  of  sci- 
entific physiological  explanation  like  that 
of  dividing  the  endocrine  glands  into 
"hypertensive"  and  "hypotensive,"  or  of 
a  pathological  explanation  like  that  which 
attributes  the  hypertrophied  heart  in  the 
status  lymphaticus  with  a  large  thymus  to 

47 E.  Gley  and  Alf.  Quinquaud,  "Action  de  l'extrait 
thyroidien  sur  la  secretion  surrenale, "  C.  B.  de  I' Ac.  des' 
sciences,  June  30,  1913,  CLVI,  p.  2013;  see  also  Arch. 
internationales  de  physiol.,  1914,  XIV,  p.  152-174. 


CHAEACTERISTICS  OF  GLANDS   129 

an  excessive  thymus  secretion  (?),  or  of 
the  use  of  a  new  medicinal  agent  like  that 
of  ''hormonal." 

In  reality,  because  many  of  these  ex- 
tracts have  an  action  on  the  arterial  pres- 
sure, one  does  not  have  the  right  to  con- 
clude, without  further  investigation,  that 
these  organs  discharge  hypertensive  or 
hypotensive  substances  into  the  blood.  It 
was  not  even  noted  that  in  order  to  obtain 
appreciable  phenomena,  it  is  often  neces- 
sary to  inject  quantities  of  extract  cor- 
responding to  several  of  the  organs  from 
which  they  were  obtained.48 

We  thus  see  how  many  assumptions  and 
hypotheses  exist  in  the  theory  of  the  patho- 
genesis of  disturbances  in  the  functions  of 
the  endocrine  organs  cited  above.  We 
must  admit  the  discharge  into  the  venous 
blood  from  the  thymus  of  a  substance 
which  lowers  arterial  pressure  and  accel- 
erates the  heart  action,  then  the  normal 

49  Cf.  Aldo  Patta,  loc.  tit. 


130    THE  INTERNAL  SECRETIONS 

antagonism  of  this  substance  to  adrenalin, 
and  finally  that  in  the  status  lymphaticus 
there  is  suprarenal  insufficiency.  It  is  need- 
less to  add  that  the  fact  lying  at  the  base  of 
all  this  reasoning — the  reality  of  an  inter- 
nal secretion  of  the  thymus — is  not  as  yet 
in  the  least  proved. 

Hormonal  medication  may  be  cited  as  a 
good  example  of  the  point  we  want  to  raise. 
As  is  well  known,  it  is  based  solely  on  the 
fact  that  the  extract  of  the  duodenal  mu- 
cous membrane  has  the  property  of  excit- 
ing intestinal  peristalsis.49  The  same  is 
true  of  splenic  extract.  As  a  result  of 
these  facts,  the  supposition  that  a  hormone 
is  present  in  these  extracts  was  immedi- 
ately advanced.  Even  disregarding  the 
fact  that  these  extracts  may  contain  al- 
bumoses,  and  all  physiologists  know  that 

49  See  Zulzer,  Dohbn  and  Marxer,  "Specifische  Anre- 
gung  der  Darmperistaltik  durch  intravenose  Injektion 
des  Peristaltikhormons"  (Berl.  Min.  Woch.,  1908,  No. 
46);  Zulzer,  "Die  Hormontherapie :  I.  Das  Peristaltik- 
hormon,,  (Therapie  der  Gegenwart,  May,  1911,  p.  197). 


CHARACTERISTICS  OF  GLANDS   131 

albumoses  provoke  more  or  less  violent  in- 
testinal movements,  how  could  one  fail  to 
think,  before  forming  any  theory,  of  col- 
lecting the  blood  from  the  intestinal  or 
splenic  veins  of  an  animal  in  a  sufficient 
quantity,  and  investigating  if  this  blood, 
injected  into  another  animal  of  the  same 
species,  manifests  the  same  properties  as 
the  extract.  Furthermore,  grave  accidents 
have  already  been  mentioned  following  the 
use  of  hormonal :  considerable  lowering  of 
arterial  pressure,  which  is  not  astonishing 
to  any  one  who  knows  the  hypotensive  ac- 
tion of  intestinal  extracts,  with  a  tendency 
to  collapse,  dyspnea,  feeble  heart  action, 
etc.50  Two  cases  of  death  have  even  been 
observed.51  It  is  quite  possible  that  the  in- 
testinal venous  blood  has  been  found  to 

50  Dittler  and  Mohr,  Munch,   med.   Woch.,  Nov.   14, 

1911,  p.    2427;    Hesse,  Deutsch.  med.   Woch.,  April  4, 

1912,  p.  525;  Kosenkranz,  Miinch.  med.  Woch.,  April  22, 
1912,  p.  931;  Wolf,  Ibid.,  May  14,  1912,  p.  1107,  etc. 

MA.  T.  Jurasz,  Deutsch.  med.  Woch.,  May  30,  1912, 
p.  1037;  Mohr,  Wien.  Uin.  Woch.,  May  16,  1912,  p.  840 
(case  of  death  observed  by  Madlener). 


132    THE  INTERNAL  SECRETIONS 

have  an  excitatory  action  on  the  muscula- 
ture of  the  intestine ;  yet,  should  this  prove 
to  be  the  case,  we  must  assure  ourselves 
that  we  are  dealing  with  a  specific  action, 
as  Ziilzer  claimed,  and  not  with  the  general 
action  of  any  of  the  smooth  muscular 
fibers.  The  word ' '  hormone ' '  is  being  very 
much  abused  while  this  demonstration  is 
being  awaited.  And  how  many  other  ex- 
amples could  we  not  give?  We  have  al- 
ready seen  (p.  64)  exactly  what  must  be 
understood  by  this  word,  and  I  will  return 
to  it  later  on  (pp.  135  and  143).  This  ex- 
tension— abusive  because  it  is  made  with- 
out experimental  basis — of  a  perfectly 
clear  and  precise  term  would  in  itself  suf- 
fice to  show  what  dangers  may  follow  the 
method  of  organic  extracts  when  it  is  ex- 
clusively and  recklessly  applied. 

What  we  must  nevertheless  retain  from 
the  results  of  researches  carried  out  with 
organic  extracts,  is  that  among  these  sub- 
stances some  may  be  found  which,  thanks 


CHAEACTEKISTICS  OF  GLANDS   133 

to  their  physiological  properties,  consti- 
tute therapeutic  agents  of  value.  It  has 
been  stated  that  various  extracts  of  value 
— testicular,  pancreatic,  thyroid,  thymus 
and  prostate — augment  the  contractions  of 
the  bladder ; 52  that  extracts  of  the  hypoph- 
ysis (posterior  lobe),  the  pineal  gland, 
the  thymus  or  the  corpora  lutea,  injected 
intravenously,  provoke  the  secretion  of  the 
mammary  glands ; 53  and  it  would  be  easy 
to  mention  other  observations  of  the  same 
sort  on  different  organs.  Perhaps  herein 
lie  reasons  for  the  introduction  of  the  ex- 
tracts into  pharmacology.  But  from  the 
results  of  the  pharmacodynamic  study  of 
organic  extracts  we  have  positively  no 
right  to  draw  conclusions  as  to  the  physi- 
ological activities  of  these  organs.     How 

D Isaac  Ott  and  J.  C.  Scott,  "The  Action  of  Animal 
Extracts  upon  the  Bladder"  (Monthly  Cyclopedia  and 
Med.  Bull,  July,  1911). 

"Isaac  Ott  and  J.  C.  Scott,  Therapeutic  Gaz.,  May 
and  Nov.,  1912,  pp.  310  and  761;  E.  A.  Schafer  and 
Mackenzie,  Proc.  of  the  Boyal  Soc,  1911. 


134    THE  INTEENAL  SECRETIONS 

could  effects  obtained  through,  experimen- 
tal violence  confer  this  right?  The  true 
criterion  of  the  function  of  internal  secre- 
tion is  the  presence  of  a  specific  product  in 
the  venous  blood  of  a  gland. 

II.      PRINCIPAL    DISTINCTIVE    CHARACTERISTICS 
OF  THE  PRODUCTS  OF  INTERNAL  SECRETION 

The  products  of  internal  secretion  differ 
very  much  from  one  another  in  their  na- 
ture, but  above  all  in  their  mode  of  action 
and  their  physiological  destination.  We 
may  classify  them  in  the  following  cate- 
gories. 

(1)  Nutritive  Substances. — A  first 
category  is  that  of  substances  which  serve 
as  nutritive  materials,  either  for  energy 
production  (glycose  of  hepatic  origin,  fats) 
or  for  blood  repair  ( specific  proteins  of  the 
blood). 

(2)  MORPHOGENETIC    SUBSTANCES    (HaR- 

mozones). — Another  category  which  nat- 
urally follows  the  one  above,  includes  sub- 


CHARACTERISTICS  OF  GLANDS  135 

stances  serving  as  tissue  builders,  in  the 
course  of  ontogenetic  development,  or 
morphogenetic  substances.  Neither  his- 
tological nor  chemical  facts  have  provided 
us  with  this  notion;  it  is  the  result  of  a 
large  number  of  physiological  experiments 
(experiments  on  extirpation  of  organs) 
and  numerous  anatomo-clinical  proofs. 
Thus  was  formed  the  group  of  glands  of 
morpho  genie  action  (interstitial  gland  of 
the  testicle,  corpora  lutea,  thyroid, hypoph- 
ysis and  thymus),  or  better,  of  secretory 
products  of  morphogenic  chemical  action, 
whose  nature  and  mode  of  action  are  both 
unknown  (by  catalysis,  by  a  process  anal- 
ogous to  chemiotaxis,  by  fixation  of  min- 
eral materials,  etc.),  and  for  which  I  have 
proposed  the  name  harmozones  (from 
Greek  dP)uo£a),  I  rule,  I  direct). 

I  think  that  these  distinctions  are  indis- 
pensable. It  is  impossible  to  qualify  as 
hormones,  as  is  done  only  too  often  at 
present,  all  the  products  of  internal  secre- 


136    THE  INTERNAL  SECRETIONS 

tion.  How  many  physicians  and  even 
physiologists  have  permitted  themselves 
to  be  carried  away  by  this  confusion!  "A 
science  is  a  well  made  language."  Con- 
fusion of  terms  can  only  be  followed  by 
confusion  of  ideas.  A  hormone  is  nothing 
but  an  exciting  agent,  according  to  its 
etymology  and,  moreover,  according  to  the 
meaning  that  the  creator  of  the  term, 
Starling,  assigned  it.  The  word  is  not 
suited  to  anything  but  what  had  previously 
been  termed  specific  functional  excitants 
(see  pp.  62-65).  In  what  respect  is  the 
hepatic  glycose  a  hormone?  Such  a  de- 
nomination is  inapplicable  to  that  sub- 
stance, being  of  the  type  of  those  which 
constitute  the  first  category  of  endocrine 
products ;  namely,  nutritive  materials. 

It  is  no  longer  possible,  at  least  in  ac- 
cordance with  what  we  actually  know  of 
the  physiological  action  of  morphogenetic 
substances,  to  confound  these  with  hor- 
mones.    Can  we,  for  example,  class  as  a 


CHARACTERISTICS  OF  GLANDS  137 

hormone  that  substance,  of  testicular  ori- 
gin, which  regulates  the  development  of 
the  skeleton  in  such  a  manner  that,  subject 
to  its  influence,  the  bones  grow  in  length? 
And  how  are  we  to  explain  that  disease  or 
extirpation  of  the  hypophysis  is  followed 
by  a  disproportionate  development,  in 
length  and  in  thickness,  of  the  extremi- 
ties, the  skeleton,  the  soft  parts  and  the 
face;  that  hypofunction  of  the  thymus 
renders  the  bones  shorter,  thinner  and 
more  fragile.  The  fact  that  after  castra- 
tion the  epiphyses  persist  explains  noth- 
ing, and  needs,  on  the  contrary,  to  be  ex- 
plained itself.  This  persistence  of  the  con- 
necting cartilages  also  occurs  in  dethy- 
roidated  animals  and  in  myxedematous 
children,  in  whom  the  development  of  the 
bones,  particularly  of  the  long  bones,  is 
arrested,  and  in  whom  the  development  of 
the  osseous  system  is  improved  by  thyroid 
treatment.  We  cannot  admit  that  the  ac- 
tion of  the  two   substances,  thyroid  and 


138    THE  INTERNAL  SECRETIONS 

diastema,54  act  in  the  same  maimer, 
since  the  results  of  the  suppression  of  the 
two  secretions  are  the  reverse  of  one  an- 
other. Besides,  can  we  give  a  clear  ac- 
count of  the  process  of  the  growth  of  bone? 
Several  histological  and  chemical  con- 
ditions are  necessary:  the  proliferation 
of  the  marrow  of  the  bone,  the  division  of 
the  cartilaginous  cells,  the  processes  of  os- 
sification and  calcification.  If  we  ascribe 
to  the  substance  of  the  thyroid  an  excita- 
tory action,  on  what  part  of  this  complex 
process  is  this  action  exerted?  And  in 
what,  for  example,  does  an  excitation  of 
the  process  of  ossein  formation  consist? 
Like  difficulties  are  encountered  while  try- 
ing to  explain  the  osseous  alterations  in 
acromegaly.  Are  we  to  suppose  that  the 
growth  of  the  skeleton  in  young  sufferers 
from  acromegaly — in  whom,  it  has  been 

M  From  dLd<rT7]fia,  interstice,  a  word  used  by  P.  Ancel 
and  P.  Bouin  to  designate  the  interstitial  gland  of  the 
testicle. 


CHARACTERISTICS  OF  GLANDS  139 

maintained,  the  development  of  the  genital 
organs  is  arrested — depends  not  on  an  ac- 
tion of  the  hypophysis  itself  (hyperfunc- 
tion  of  the  pituitary?)  but  on  a  diaste- 
matic  insufficiency?  Without  insisting  on 
the  hypothetical  character  of  this  explana- 
tion, the  difficulty  here  would  be  that  the 
growth  in  length  of  the  bones  of  castrated 
animals  and  eunuchs  does  not  in  the  least 
resemble  the  hypertrophy  of  the  extremi- 
ties of  acromegalics.  Is  it  not  more  pru- 
dent for  the  time  being  to  avoid  combining 
all  these  products  of  secretion,  to  refuse  to 
identify  the  substances  having  a  morpho- 
genetic  action  with  the  functional  excitants 
proper,  or  hormones?  When  we  better 
understand  the  conditions  and  causes  of 
ossification,  as  well  as  the  influences  which 
may  be  exerted  on  one  or  the  other,  we  will 
perhaps  be  in  a  position  to  determine  ex- 
actly the  mode  of  action  of  the  substances 
coming  from  the  thyroid,  testicle  or  hy- 
pophysis.   Meanwhile,  the  name  of  harmo- 


140    THE  INTERNAL  SECRETIONS 

zones  expresses  a  fact,  without  anticipating 
anything  as  to  its  nature. 

Not  only  the  development  of  the  skeleton 
is  regulated  by  internal  secretions.  The 
development  of  the  genital  tract  and  its  ac- 
cessory glands  is  subject,  in  the  male,  to 
the  action  of  the  interstitial  glands,  and  in 
the  female,  to  that  of  the  corpora  lutea, 
which  also  regulate  the  development  of 
the  breasts.  Finally,  the  development  of 
the  germinative  gland  depends,  at  least  in 
part,  on  the  action  of  the  thyroid,  as  well 
as  of  the  central  nervous  system.  We  have 
no  idea  of  the  nature  of  the  phenomena 
which  take  place  in  any  of  these  organs 
under  the  influence  of  the  secretions  men- 
tioned. We  may  say  that  they  are  phe- 
nomena of  assimilation,  but  that  does  not 
advance  us  at  all. 

Here  we  might  set  a  new  problem  of  a 
totally  different  order,  and  which,  further- 
more, should  occupy  biologists :  if  we  now 
understand  at  least  a  part  of  the  mechan- 


CHARACTERISTICS  OF  GLANDS  141 

ism  of  development  (i.  e.,  the  action  of  in- 
ternal secretions),  we  do  not  explain  better 
than  by  the  above  why  this  development 
stops  at  a  given  moment.55  Let  us  sup- 
pose that  the  interstitial  gland  of  the  tes- 
ticle, or  another  gland  with  similar  func- 
tions, is  reduced  in  functional  activity.  Is 
the  quantity  of  active  substance  that  it 
sends  to  the  organ  on  which  it  acts  conse- 
quently diminished  1  But  there  is  no  proof 
of  such  a  functional  diminution;  and,  fur- 
thermore, since  these  substances  act  in 
very  small  doses,  we  must  under  such  cir- 
cumstances   assume   the    almost   absolute 

63  Although  we  have  no  space  to  examine  them  here, 
it  is  not  without  interest  to  mention  the  relations  that 
Eubner  has  established  between  the  consumption  of 
energy,  the  intensity  of  growth  and  the  duration  of  life, 
his  very  penetrating  ideas  drawn  from  the  laws  of 
growth  and  the  almost  mathematical  cessation  of  the 
latter.  (Cf.  Eubner,  "Das  Problem  der  Lebensdauer, ' ' 
Miinchen,  1910.)  Also  of  great  value  on  this  subject  is 
a  recent  study  by  Yves  Delage  on  the  progressive  de- 
crease in  physiological  fecundity  being  proportional  to 
the  increase  in  height.  (Eevue  scientifique,  July  19, 
1913,  LI,  65-69.) 


142    THE  INTEENAL  SECBETIONS 

suppression  of  their  functioning.  The 
problem  is  not  decided. 

I  therefore  maintain  that  there  are  endo- 
crine products  which  cannot  be  qualified 
as  hormones ;  all  that  we  know  at  present 
concerning  morphogenetic  substances  is 
that  they  regulate  development.  Starling 
has  called  hormones  "chemical  messen- 
gers," but  the  two  expressions  are  not 
synonymous.  All  hormones  are  endocrine 
products,  chemical  messengers,  but  all  en- 
docrine products,  i.  e.,  all  chemical  messen- 
gers, are  not  hormones.  The  remark  which 
follows  corroborates  this  distinction  fur- 
ther. 

The  name  of  harmozones  may,  indeed,  be 
applied  to  those  substances  which  act  as 
modifiers  of  chemical  processes  in  which 
they  appear  to  play  a  role  analogous  to 
that  of  diastases :  the  substances,  secreted 
by  the  pancreas,  which  regulate  the  gly- 
cose-forming  function  of  the  liver,  either 
by  transforming  the  glycose  into  glycogen 


CHAEACTERISTICS  OF  GLANDS  143 

(diastatic  action),  or  by  diminishing  the 
transformation  of  glycogen  into  glycose, 
or  by  destroying  the  glycose  in  the  tissues, 
and  particularly  in  the  muscles  (by  a  fer- 
ment adjuvant  to  the  glycolytic  diastase) ; 
and  the  hepatic  antithrombin  which  op- 
poses the  process  of  intranuclear  coagula- 
tion as  in  the  coagulation  of  blood  in  vitro. 

(3)  The  Hormones. — A  third  category 
is  reserved  for  the  substances  which  pro- 
voke functional  activity  and  consequently 
play  the  role  of  excitants.  These  are  the 
true  hormones,  or  specific  functional  ex- 
citants. They  may  be  divided  into:  (1) 
chemical  hormones  (excitants  of  chemical 
phenomena) ;  and  (2)  physiological  hor- 
mones (excitants  of  physiological  phenom- 
ena, or  functions). 

The  first  class  is  represented  by  the  sub- 
stance produced  in  the  spleen,  which  acti- 
vates trypsin,  and  by  the  substance  se- 
creted by  the  thyroid  in  so  far  as  it  modi- 
fies   general    nutrition,    augmenting    the 


144    THE  INTERNAL  SECRETIONS 

nitrogenous  and  respiratory  exchanges,56 
and  which  therefore  reveals  itself  as  a 
powerful  agent  of  disassimilation;  or  does 
the  thyroid  secrete  several  substances  of 
opposed  trophic  roles?  We  have  no  in- 
formation on  this  subject.57 

The  physiological  hormones  are  secretin, 
adrenalin  and  the  substances  (of  as  yet 
uncertain  origin,  see  above,  p.  101)  which 
provoke  the  secretion  of  milk.  Perhaps 
we  must  add  the  product  of  the  secretion 
of  the  prostate,  according  to  the  experi- 
ments of  A.  Vichnevsky  (1909).  The  lat- 
ter, in  the  laboratory  of  Mislavsky,  has 

80  It  is  known  that  it  increases  them  much  more  in 
myxedematous  than  in  normal  individuals  (Magnus- 
Levy). 

67  Other  organic  extracts,  those  of  the  testicles,  ovaries, 
hypophysis,  etc.,  appear  to  also  modify  the  mineral,  hy- 
drocarbon and  nitrogen  exchanges.  I  have  not  touched 
upon  this  question.  Both  the  literature  of  the  subject 
and  a  discussion  of  it  will  be  found  in  "Probleme  der 
physiol.  und  pathol.  Chemie, "  by  O.  von  Furth  (Leip- 
zig, 1912),  and  in  the  "Handbuch  der  speziellen  Pathol, 
des  Hams,"  by  F.  Blumenthal  (Berlin,  1913);  also  in 
Biedl's  book  and  the  article  by  Magnus-Levy  cited  on 
p.  68. 


CHABACTERISTICS  OF  GLANDS  145 

shown  that  the  secretion,  and  not  the  ex- 
tract of  the  prostate,  obtained  by  the  ex- 
citation of  the  fibers  of  the  prostatic  plexus, 
provokes  movements  of  the  spermatozoa 
mnch  more  intense  than  those  caused  by 
various  saline  solutions  or  by  the  serum 
of  the  animal  experimented  on,  etc.  As 
for  the  "gastric  secretion"  studied  by  Ed- 
kins,58  and  the  hypertensive  substance  of 
renal  origin  (R.  Tigerstedt),59  there  is  not 

08 E.  A.  Edkins,  "The  Chemical  Mechanism  of  Gas- 
tric Secretion"  {J.  of  Physiol,  1906,  XXXIV,  pp.  133- 
134). 

08  R.  Tigerstedt  and  P.  G.  Bebgmann,  "Niere  und 
Kreislauf  "  (Skand.  Arch,  fiir  Physiol,  1898,  VIII,  223- 
271).  In  the  last  edition  of  his  "Lehrbuch  der  Physiol- 
ogic des  Menschen"  (7th  ed.,  Leipzig,  1913),  Tigerstedt 
recognized  that  it  has  not  been  demonstrated  that  the 
hypertensive  substance  of  the  renal  extract  passes  in 
the  venous  blood  of  the  kidney.  "Ob  die  Wirksame 
Substanz  auch  im  Nierenvenenblute  vorkommt,  ist  noch 
nicht  bestimmt  entschieden ' '  (loc.  eit.,  vol.  I,  p.  523). 
On  the  subject  of  an  internal  secretion  of  the  kidneys 
(Brown-Sequard),  we  may  for  the  meantime  recall  the 
experiments  of  E.  Meyer,  of  Nancy  (Arch,  de  pliysiol, 
1893,  pp.  760-765),  which  show  that  the  injection  of 
renal  venous  blood  into  a  uremic  dog  (by  double  nephrec- 
tomy) suppresses  the  periodic  respiration  and  reestab- 
lishes the  normal  respiratory  rhythm.     A.  Pi  y  Stjneb 


146    THE  INTEENAL  SECRETIONS 

sufficient  experimental  justification  for 
considering  them  as  products  of  internal 
secretion. 

(4)  The  Pakhokmones. — Finally,  there 
remains  one  more  class  of  secretory  prod- 
ucts. In  it  are  included  excretory  prod- 
ucts, such  as  that  which  the  liver  elaborates 
in  transforming  toxic  substances  like  am- 
monia and  the  amino-acids  or  like  the 
phenols  into  urea  and  phenylsulphates, 
compounds  which  are  almost  harmless.  It 
is  known  as  the  antitoxic  function  of  the 
liver.  Must  we  place  urea  among  the  hor- 
mones ?  This  question  confronts  us  all  the 
more  since  there  are  other  similar  products 
that  many  physiologists,  following  Bayliss 
and  Starling,  have  included  in  the  class  of 
hormones.    A  typical  one  is  carbonic  acid, 

(1905)  has  maintained  that  the  kidney  is  not  a  true 
internal  secretory  gland,  but  a  gland  having  an  anti- 
toxic function,  which  is  exercised  principally  on  the 
blood  of  uremics;  the  latter  offer  an  obstacle  to  the 
urinary  secretion  and  the  injection  of  renal  extract  from 
uremic  animals  provokes  diuresis. 


CHARACTERISTICS  OF  GLANDS   147 

which  excites  the  respiratory  center  in  the 
bulb.  This  compound  has  even  been  con- 
sidered as  an  example  of  those  substances 
by  which  the  neurochemical  correlations 
are  established.  Carbonic  acid  is  produced 
in  large  quantities  by  the  work  of  the  mus- 
cles and  its  accumulation  in  the  blood  would 
be  noxious,  but  it  augments  the  activity  of 
the  respiratory  center,  increasing  the  fre- 
quency of  respiration  with  resulting  in- 
crease in  the  pulmonary  ventilation  and 
consequently  of  the  quantity  of  oxygen  ad- 
mitted into  the  blood,  and,  finally,  regu- 
lating the  oxygen  content  of  the  blood 
and  of  respiration.  As  for  urea,  we  now 
know  that  this  is  only  a  very  slightly  toxic 
substance,  the  reverse  of  carbonic  acid.  It 
has,  however,  one  property  in  common  with 
the  latter,  namely,  to  excite  the  cells  of  the 
kidneys.  Moreover,  it  does  this  not  indi- 
rectly, through  the  medium  of  the  nervous 
system,  but  the  cells  of  that  excretory  or- 
gan by  which  it  is  eliminated  are  directly 


148    THE  INTERNAL  SECRETIONS 

affected.    The  diuretic  action  of  urea  is  in 
fact  well  known. 

But  there  is  no  reason  for  considering 
these  excretory  products  as  true  hormones. 
This  is  an  opinion  that  I  have  already 
maintained  and  which  is  also  held  by  S.  J. 
Meltzer.60  My  reasons  are:  The  concep- 
tion of  a  gland,  as  I  showed  as  far  back  as 
1893,  is  clear  and  precise  only  in  case  it 
conveys  a  physiological  notion.  It  must 
show  a  specialization  of  the  secretory  cellu- 
lar elements  and  the  destination  of  the 
products  secreted.  Otherwise,  all  cells 
might  be  termed  glandular,  for  there  is 
no  cell  which  does  not  elaborate  a  sub- 
stance that  it  uses  or  discharges  into  the 
blood,  and  we  would  thus  come  to  confuse 
"secretion  with  the  acts  of  cellular  nutri- 
tion themselves. ' ' 61     What,   then,  is  the 

60 S.  J.  Meltzek,  "Animal  Experimentation  in  Eola- 
tion to  our  Knowledge  of  Secretions,  Especially  Internal 
Secretions"  (Proc.  of  the  Pathol.  Soc.  of  Phil,  1910, 
N.S.,  XIII,  170-196). 

61 E.     Gley,     ' '  Conception     et     Classification     physi- 


CHARACTERISTICS  OF  GLANDS   149 

true  physiological  nature  of  products  elab- 
orated in  real  secretory  elements?  They 
are  not  substances  arising  from  nutritive 
transmutations?2  the  resulting  material 
does  not  become  an  integral  part  of  the 
protoplasm.  The  secretory  cells  manufac- 
ture it  for  special  purposes ;  not  for  them- 
selves but  for  other  organs  and  for  the 
general  functions  of  the  organism,  all 
parts  of  which  form  a  solidarity.  The 
destination  of  the  secreted  products  is,  in 
fact,  no  less  characteristic  than  their  na- 
ture. These  products  are  utilized  for 
other  objects  than  those  of  the  cells  which 
have  manufactured  them  and  altogether  in 
other  parts  of  the  organism.  It  is  remark- 
able that  histologists  have  arrived  at  an 
analogous  conception  of  a  gland.63 

ologiques  des  glandes"  (Bevue  seient.,  July  1,  1893, 
LII,  p.   8). 

63  The  terms  nutritive  transmutations  and  functional 
transmutations  are  due  to  Charles  Bouchard. 

"See  A.  Nicholas,"  Contribution  a  l'6tude  des  cellules 
glandulaires "  (Jour,  intern,  d'anat.  et  de  physiol.,  1891, 


150    THE  INTERNAL  SECRETIONS 

From  this  point  of  view,  what  is  car- 
bonic acid?  It  is  the  excretion  of  the 
nutritive  transmutations  of  a  large  num- 
ber of  cellular  elements,  muscular  cells 
and  glandular  cells ; 64  it  is  in  no  wise  a 
specialized  product,  it  is  a  general  sub- 
stance resulting  from  the  katabolism  of  the 
tissues.  What  is  its  destination!  It  is 
principally  a  product  of  excretion.  And 
what  is  urea  1  Most  assuredly  it  is  mainly 
a  substance  formed  in  and  by  the  hepatic 
cells,  but  it  has  been  established  that  it  is 
formed  elsewhere  in  small  quantities.  It 
is  also  a  waste  product,  an  excretion.  It 
is  true  that  these  substances,  once  in  the 
blood,  manifest  physiological  actions,  or 
vital  activities.     But  they  have  not  been 

VIII,  279);  Laguesse,  "Les  glandes  et  leur  definition 
histologique "  (Semaine  med.,  May  11,  1895,  p.  213);  A. 
Pettit,  "S6cr6tion  externe  et  secretion  interne"  (La 
Presse  med.,  July  12,   1913). 

84  An  excellent  series  of  investigations  on  the  produc- 
tion of  carbon  dioxid  by  glands  has  been  published  by 
the  English  physiologists  Bancroft  and  Brody  and  their 
collaborators. 


CHAEACTERISTICS  OF  GLANDS   151 

excreted  especially  in  order  that  they 
might  perform  these  actions.  The  reverse 
is  true  of  true  secretions.  And,  further- 
more, could  it  not  be  that  products  of  dis- 
integration have  no  physiological  action? 
Is  this  not  so  in  the  case  of  the  phenyl- 
sulphates,  which  are  also  formed  by  the 
hepatic  cells  ?  And  is  this  not  also  true,  at 
least  as  far  as  our  actual  information  goes, 
in  the  case  of  uric  acid  in  birds,  similarly 
elaborated  in  the  liver,  to  be  taken  up  by 
the  blood  and  eliminated  by  the  kidneys? 
A  particular  sensibility  of  the  bulb  for 
carbonic  acid  has  been  invoked,  a  sort  of 
adaptation  of  the  organ  to  its  excitant,  as 
one  might  invoke  a  particular  sensibility 
of  the  renal  cells  to  urea.  But  "what  does 
this  specific  irritability  mean?"  Melt- 
zer 65  asks  justly,  ' '  only  that  the  organism 
protects  itself  by  rendering  the  respiratory 
center  so  sensitive  to  this  dangerous  ex- 
cretory product  that  the  surplus  automati- 
MLoc.  tit. 


152    THE  INTERNAL  SECRETIONS 

cally  activates  an  efficacious  mechanism 
for  its  rapid  elimination."  And  Meltzer 
adds,  not  without  humor :  '  *  "We  know  that 
the  animal  organism  is  provided  with  nu- 
merous defenses  against  the  invasion  of 
bacteria  or  of  other  harmful  agents.  Is 
the  existence  of  these  means  of  defense 
within  the  body  a  proof  that  these  bacteria 
and  deleterious  substances  form  a  part  of 
the  animal  economy?"  On  my  part,66  I 
have  written:  "The  excretions  resulting 
from  the  activity  of  the  cellular  elements 
.  .  .  may  well,  even  in  the  course  of  their 
elimination,  play  a  physiological  role.  .  .  . 
Thus,  carbonic  acid,  which  has  been  cited 
as  the  most  simple  of  hormones,  consti- 
tutes, in  consequence  of  a  special  irritabil- 
ity of  the  bulb  respiratory  center  towards 
this  substance,  a  stimulant  of  the  respira- 
tory movements.    But  it  is  not  in  the  least 

"'Revue  scientifique,  March  4,  1911,  p.  257  (a  lecture 
taken  from  my  course  of  1909-10  at  the  College  of 
France). 


CHARACTERISTICS  OF  GLANDS   153 

a  product  of  secretion  of  muscular  cells; 
the  production  of  carbon  dioxid  in  greater 
or  lesser  quantity  is  positively  not  one  of 
the  functions  of  muscle.  And  it  has  been 
conceived  that  other  products  of  disin- 
tegration may  likewise,  in  an  accessory 
manner,  exercise  a  physiological  action. 
On  the  other  hand,  only  the  protein  iodid 
matter  of  the  thyroid  is  secreted  by  the 
cells  of  that  gland,  only  adrenalin  is  se- 
creted by  the  adrenals,  etc.,  and  the  only 
destination  of  substances  of  this  category 
is  to  fulfil  their  specific  functional  roles. 
In  the  course  of  fulfilling  this  role  they  are 
not  otherwise  eliminated;  they  are  de- 
stroyed, as  is  the  case  with  adrenalin  and 
secretin.  Hence  we  may  consider  the  term 
hormone  as  being  too  universal  (in  the  log- 
ical sense  of  the  word)  and  not  comprehen- 
sive enough.  There  exist  at  least  two 
classes  of  functional  excitants,  different  in 
origin,  in  the  character  of  their  action 
(secondary  or  essential),  and  in  their  des- 


154    THE  INTERNAL  SECRETIONS 

tination.  At  most  we  might  apply  the  term 
parharmones  to  the  excretory  products 
which  play  only  an  accessory  role  as  ex- 
citants, reserving  the  name  of  hormones 
for  the  specific  glandular  products." 

In  the  second  edition  of  his  ' '  Innere  Se- 
kretion,"67  Biedl  does  not  believe  that  he 
can  admit  this  distinction.  "If  through 
the  medium  of  the  ordinary  end  product 
of  the  material  exchanges,"  he  says, 
"chemical  correlations  are  established  in 
the  organism,  and  if  the  exciting  action,  as 
this  term  is  understood  in  the  concept  of 
hormone,  is  due  to  this  product,  then  we 
must  consider  it  as  a  hormone  without  con- 
sideration of  its  origin,  composition  and 
destination."  It  seems  to  me  that  this 
contains  no  adequate  reply  to  the  argu- 
ments of  Meltzer  and  myself ;  he  simply 
maintains  that  it  is  sufficient  for  an  or- 
ganic extract  to  have  an  excitatory  action 
in  order  that  it  be  included  among  the  hor- 

87  Vol.  I,  p.  11. 


CHARACTERISTICS  OF  GLANDS    155 

mones,  without  taking  account  of  its  origin, 
nature  and  destination.  But  I  insist  that 
we  cannot  satisfactorily  define  products  of 
secretion  unless  we  take  into  account  their 
origin  and  destination.  On  this  point  I 
am  in  accord  with  the  most  competent  his- 
tologists  as  well  as  with  numerous  physiol- 
ogists. Is  it  not  sufficient  to  designate  as 
parharmones  those  excretory  products 
which  have  a  physiological  action? 

How  many  products  of  excretion  mani- 
fest, while  being  eliminated,  their  physio- 
logical properties  and  serve  for  the  estab- 
lishment, rapid  and  transitory,  though  ca- 
pable of  being  renewed,  of  a  chemical  or 
neurochemical  correlation,  is  another  ques- 
tion which  no  one  can  cast  into  doubt. 
"The  example  of  carbon  dioxid,"  says 
Biedl,68  "which  is  not  unique  but  which  is 
one  of  the  best  studied,  shows  in  an  obvious 
manner  that  the  products  of  the  material 
exchanges    play    an    important    part    by 

88 ' '  Innere  Sekretion, ' '  2nd  Edit.,  vol.  I,  p.  12. 


156    THE  INTERNAL  SECRETIONS 

means  of  chemical  correlations."  I  do  not 
gainsay  this.  Undoubtedly,  the  conception 
of  hormones  is  inseparable  from  that  of 
functional  correlations;  but  functional 
correlations  may  be  effected  by  substances 
other  than  hormones;  this  term  being  re- 
served for  the  specific  excitants,  products 
of  secretion. 

(5)  The  Distinctive  Characteristics 
of  the  Endocrine  Products. — All  these 
products  present  certain  properties  in 
common  and  some  differences  which  are 
important  and  deserve  elucidation. 

1.  Between  the  substances  of  the  first 
category  (nutritive  substances)  and  those 
of  the  two  following  classes  (harmozones 
and  hormones)  there  exists  an  important 
difference:  The  nutritive  substances  in- 
tended for  energy  production  or  tissue  re- 
pair (Verbrauchssekrete,  following  the 
nomenclature  of  Biedl),  i.  e.,  for  transmu- 
tation of  matter — are  discharged  into  the 
blood  stream  in  quite  considerable  quanti- 


CHARACTERISTICS  OF  GLANDS    157 

ties;  this  is  a  matter  of  course,  for  these 
are  the  substances  which  carry  to  the  or- 
gans energy-producing  and  combustive  ma- 
terial, and  the  organs  always  have  need  of 
one  and  the  other  in  considerable  quan- 
tities. 

Morphogenetic  substances  and  hor- 
mones, on  the  contrary,  act  in  very  minute 
doses ;  they  are  substances  which  appear  to 
act  after  the  fashion  of  a  nervous  excita- 
tion or  of  a  diastatic  action ;  they  bring  no 
energy  to  the  tissues  or  organs  which  they 
influence,  but  they  only  liberate  preexist- 
ing energy;  they  regulate  anabolism  and 
katabolism,  construction  and  disintegra- 
tion of  the  tissues. 

2.  In  addition  to  this  difference  we  have 
a  resemblance :  not  only  hormones  proper, 
as  Biedl  has  observed,69  have  the  charac- 
teristic of  not  being  antigens  70  and  not  giv- 

WA.  Biedl,  "Innere  Sekretion,"  2nd  Edit.,  Vol.  I, 
p.  1. 

"Bayliss  and  Starling  were  the  first  (1906),  I  think, 
to  indicate  this  important  characteristic  of  hormones. 


158    THE  INTERNAL  SECRETIONS 

ing  rise,  following  their  injection  into  the 
blood,  to  antibodies ;  this  is  also  true  of  the 
substances  having  a  morphogenic  actionf 
and  the  nutritive  materials,  such  as  gly- 
cose,  specific  albumins,  etc.  "The  only 
characteristic  which  generally  distin- 
guishes hormones,"  says  Biedl,  "is  at  the 
present  state  of  our  knowledge  a  negative 
one."  And  this  characteristic,  undoubt- 
edly negative,  but  important,  applies  to  all 
true  internal  secretions ; 71  it  is  like  a  sig- 
nature, being  essential  to  action;  their 
penetration  into  the  internal  medium  does 
not  provoke  a  reaction  which  would  anni- 
hilate their  effects.  The  importance  of  this 
fact  is  a  consequence  of  what  has  been  said 
about  tachyphylaxia. 

3.     One  of  the  important  characteristics 

71  However,  the  following  curious  fact  has  been  ob- 
served (Abderhalden  and  Slavu,  1909;  A.  Frohlich, 
1909)  :  Successive  injections  of  artificial  suprarenin  (syn- 
thetic adrenalin)  immunize  against  considerable  doses 
of  extractive  adrenalin.  Artificial  suprarenin  is  a  sub- 
stance which  does  not  exist  in  the  organism. 


CHARACTERISTICS  OF  GLANDS   159 

of  hormones  (and  also  of  harmozones)  is 
their  specificity  of  origin,  of  action  and  of 
function;  that  is  to  say,  anatomically  and 
physiologically,  but  not  zoologically.  The 
products  which  are  secreted  and  endowed 
with  an  elective  action  come  from  a  certain 
organ  and  only  from  that  organ;  but  no 
matter  from  what  species  of  animal  they 
are  derived,  they  exert  their  action  on  ani- 
mals of  other  species. 

Is  this  specificity  absolute?  We  cannot 
here  enter  into  a  discussion  of  the  doctrine 
of  cellular  specificity,  or  raise  in  opposi- 
tion to  the  theory  of  predetermination,  or 
preformation  (Weismann,  Bard,  Hanse- 
mann,  etc.),  that  of  epigenesis  (Hertwig, 
Wilhelm  Roux,  Wilson,  Delage,  etc.).  Let 
us  only  examine  the  facts  within  the  do- 
main of  internal  secretions.  As  a  result 
of  castration  the  respiratory  exchanges  are 
diminished,  both  in  the  male  and  in  the 
female ;  they  may  be  enhanced  again  by  the 
administration  of  ovarian  or  testicular  ex- 


160    THE  INTERNAL  SECRETIONS 

tract  (A.  Loewy  and  P.  F.  Richter,  1899), 
but  only  those  particular  extracts  have 
that  action ;  thyroid  extract  does  not  have 
it  according  to  the  experiments  of  Loewy 
and  Richter.  Finally,  this  substance  is 
also  specific  considering  that  it  acts  only 
on  castrated  animals.  Evidently,  the  pro- 
found difference  between  the  two  sub- 
stances is  not  as  yet  very  well  understood : 
both  the  one  which  comes  from  the  genital 
glands  and  the  one  from  the  thyroid  mani- 
fest the  same  physiologico-chemical  prop- 
erties and  yet  cannot  substitute  for  one 
another.  Furthermore,  the  action  of  the 
thymus  on  the  growth  of  bone  appears  to 
be  analogous  to  that  of  the  thyroid  (see  in 
particular  the  figures  published  by  M. 
Lucien  and  J.  Parisot72  on  the  arrest  of 
the  development  of  the  skeleton  observed 
in  young  dethymated  animals). 

72 M.  Lucien  and  J.  Parisot,  "Contribution  a  l'Stude 
des  f onctions  du  thymus  ..."  (Arch,  de  med.  expir., 
1910,  XXII,  98). 


CHAEACTERISTICS  OF  GLANDS   161 

Let  ns  examine  two  more  examples.  It 
now  seems  that  secretin  is  not  furnished 
exclusively  by  the  duodenojejunal  mucous 
membrane ;  it  has  been  extracted  from  the 
gastric  mucous  membrane  and  from  that 
of  the  ileum  by  other  procedures  than  the 
use  of  acids  73  (by  the  method  of  extrac- 
tion in  boiling  saline  solution).  Moreover, 
the  tissue  of  the  hypophysis  presents,  like 
that  of  the  suprarenal  bodies,  the  chromaf- 
fin reaction  and  its  extracts  have  prop- 
erties analogous  to  those  of  adrenalin — 
action  on  the  heart,  the  vessels  and  the 
pupil.  It  is  true  that,  according  to  H.  H. 
Dale  (1909),  the  mechanism  of  its  action 
on  the  smooth  muscles  74  is  not  the  same  as 
that  of  adrenalin.    This  analogy  between 

78  L.  Camus  and  E.  Gley  succeeded  in  obtaining 
it  in  small  quantities  by  the  acid  maceration  of  the 
mucous  membrane  of  the  stomach  (C.  E.  de  la  Soc.  de 
biol,  June  7,  1902,  LIV,  648). 

74  Moreover,  adrenalin  does  not  exercise  any  influence 
on  the  coronary  vessels  or  on  the  branches  of  the  pul- 
monary artery  (Dale,  1909),  the  contraction  of  which  is 
determined  by  the  extract  of  the  hypophysis.   ' 


162    THE  INTERNAL  SECRETIONS 

the  principal  physiological  properties  is 
constantly  found  and  it  is  possible,  more- 
over, that  there  is  a  relation  between  the 
constituents  of  certain  bases  having  a 
hypertensive  action,  of  the  active  principle 
of  the  hypophysis  and  of  adrenalin.75 

We  are  thus  led  to  ask  ourselves  if  the 
physiological  differentiations  have  not 
been  evolved  like  the  cellular  differentia- 
tions of  a  morphological  nature  (according 
to  the  ideas  of  the  partisans  of  epigenesis). 
That  is  to  say,  if  they  have  arisen,  not  by 
virtue  of  a  fixed  and  preestablished  plan, 
but  as  a  function  resulting  from  extrinsic 
conditions,  as  a  result  of  the  divers  exter- 
nal influences  exerted  by  elements  to  which 
they  have  been  gradually  adapted;  conse- 
quently, if  these  differences  are  something 
really  absolute,  and  if  one  could  not  find 
again,  contradictory  to  the  law  of  the  di- 
vision of  labor,  in  another  organ  the  pe- 

78  H.   H.   Dale  and  W.   E.   Dixon,   1909. 


CHARACTERISTICS  OF  GLANDS   163 

culiarities  which  characterize  or  dominate 
a  given  organ. 

Unquestionably,  these  reflections  do  not 
conflict  with  anything  we  know  about  the 
specificity  of  the  albumins  which  consti- 
tute species  and  individuals  (specific  al- 
bumins ;  see  what  is  said  above,  p.  85,  about 
absorption  and  the  internal  secretory  role 
of  -the  intestinal  epithelium)  which  are 
formed  in  the  course  of  assimilation.  As- 
similation, as  is  well  known,  is  a  form  of 
differentiation  par  excellence;  it  is  the  for- 
mation of  particles  of  living  matter  iden- 
tical with  those  which  formed  them;  identi- 
cal with  non-specific  substances,  provided 
they  contain  the  necessary  chemical  groups 
to  elaborate  the  specific  substances,  albu- 
mins of  the  blood  and,  in  each  variety  of 
cells,  the  substances  proper  to  that  cell. 
The  products  derived  from  the  cellular 
constituents  also  participate  in  this  specifi- 
city. And  it  is  this  physiology  that  ex- 
plains, besides  the  physiology  of  the  spe- 


164    THE  INTEKNAL  SECEETIONS 

cies,  that  of  the  individual ;  this,  the  physi- 
ology of  the  future,  will  be  added  to  gen- 
eral physiology,  the  physiology  of  the  par- 
ticular. This  new  field  we  are  permitted 
to  examine  through  the  facts  of  anaphy- 
laxis and  also  some  of  those  that  have  been 
observed  in  cases  of  parabiosis,  spon- 
taneous or  experimental. 

4.  The  action  of  hormones  is  not  dur- 
able. This  is  because  they  are  unstable, 
or  labile  substances;  they  disappear  rap- 
idly from  the  blood,  being  either  destroyed 
by  oxidation  or,  being  fixed  in  the  tissues 
on  which  they  act  {corpora  non  agunt,  nisi 
fixata,  Ehrlich),they  are  rapidly  destroyed 
there.  Moreover,  we  have  here  a  condition 
for  their  action  (Starling),  since,  things 
being  so,  their  effects  do  not  persist  long 
enough  to  fatigue  the  stimulated  elements ; 
the  latter  therefore  remain  able  to  receive 
new  excitations. 

5.  The  action  of  internal  secretory 
products  is  either  local  or  general.    What 


CHAEACTEKISTICS  OF  GLANDS   165 

must  we  understand  by  this?  It  is  of  no 
importance  that  the  products,  having  been 
poured  into  the  blood  stream,  are  trans- 
ported to  the  entire  organism.  This  is 
only  what  seems  to  be  the  case,  but  in  re- 
ality they  attach  themselves,  following  the 
actual  speed  of  the  circulation,  to  the  tis- 
sues with  whose  constituents  they  are  in 
chemical  correlation.  Thus,  the  local  ac- 
tion of  these  substances  is  better  compre- 
hended than  their  general  action. 

The  correlations  are  close  in  the  same 
system  of  organs.  Nothing  illustrates  this 
fact  better  than  the  formation  of  secretin 
and  the  connections  established  through 
the  intermediary  agency  of  that  substance, 
between  the  stomach  secreting  hydro- 
chloric acid  and  the  duodenum  and  jeju- 
num on  whose  mucous  membrane  the  hy- 
drochloric acid  acts,  and  the  pancreas  in 
which  secretin  excites  secretion.  This  is 
one  of  the  reasons,  among  others,  for  the 
great  biological  interest  of  Bayliss   and 


166    THE  INTERNAL  SECRETIONS 

Starling's  capital  discovery.  Likewise, 
the  chromaffin  substance  is  connected, 
physiologically  as  well  as  embryologically, 
with  the  sympathetic  system.  The  connec- 
tions between  the  liver  and  the  pancreas, 
as  we  ascend  in  the  animal  scale,  are  such 
that  nothing  is  more  natural  than  this 
functional  association  between  the  two  or- 
gans which  cause,  through  the  influence  of 
a  substance  coming  from  the  pancreas,  the 
hydrocarbon  material  to  be  mobilized  in 
the  liver. 

Let  us  now  consider  the  phenomena  of 
development.  The  diastematic  substance 
(see  p.  138)  which  regulates  the  develop- 
ment of  the  accessory  genital  glands,  and 
that  coming  from  the  corpora  lutea  also  act 
in  the  same  organic  system  to  which  they 
belong;  only  when  we  reach  the  mammary 
gland,  the  development  of  which  is  also 
under  the  influence  of  the  corpora  lutea, 
have  we  an  organ  which  cannot  be  consid- 
ered a  dependent  of  the  female  genital  sys- 


CHAEACTERISTICS  OF  GLANDS   167 

tern,  of  the  uterus,  not  only  because  of 
physiological  reasons,  but  also  for  reasons 
of  comparative  anatomy,  e.  g.,  the  external 
uterus  of  Marsupials. 

There  are,  however,  hormones  having  a 
general  action,  such  as  the  thyroid  sub- 
stance which  augments  the  intensity  of  the 
nutritive  exchanges;  a  like  effect — the  in- 
crease of  nitrogen  eliminated  and  carbon 
dioxid  excreted — is  the  result  of  a  general 
action,  carried  out  on  all  the  tissues.  And 
is  not  the  influence  exercised  on  the  devel- 
opment of  the  skeleton  by  various  internal 
secretions  the  same? 

III.  CLASSIFICATION"  OF  THE  INTERNAL  SECRE- 
TORY GLANDS  AND  THE  PRODUCTS  WHICH 
THEY  SECRETE 

The  determination  of  the  peculiarities  of 
the  endocrine  glands  and  of  the  distinctive 
characteristics  presented  by  the  products 
they  secrete  leads  to  a  classification  of 
these  organs  and  products. 


168    THE  INTERNAL  SECRETIONS 

The  latter,  in  fact,  have  certain  charac- 
teristics in  common  and  also  present  cer- 
tain differences.  They  differ  in  nature, 
mode  of  action  and  physiological  destina- 
tion. Thanks  to  these  similarities  and  dif- 
ferences, they  can  be  classified.  And  thus 
from  the  analysis  by  which  we  have  been 
enabled  to  determine  the  conditions  for, 
and  the  characteristics  of,  internal  secre- 
tions, we  rise  to  synthesis.  For  all  scien- 
tific classification  is  synthetic,  since  it  pre- 
sents its  objects  in  an  entirety,  arranged 
in  such  a  manner  as  to  reveal  the  connec- 
tions which  unite  them ;  synthesis  has  pro- 
visional truth,  more  or  less  durable  ac- 
cording to  the  state  of  development  of  the 
particular  science  at  the  given  moment. 

A  chemical  classification  of  endocrine 
products  is  absolutely  impossible ;  at  pres- 
ent we  know  the  chemical  nature  of  only  a 
few  products,  such  as  the  glycose  secreted 
by  the  liver  and  the  adrenalin  secreted  by 
the  suprarenal  capsules. 


CHARACTEEISTICS  OF  GLANDS    169 

However,  a  physiological  classification 
may  be  attempted.  That  which  I  have 
drawn  up,  therefore,  rests  only  on  physi- 
ological facts.  And  the  functional  point 
of  view  dominates  it  throughout ;  a  physi- 
ological classification  can  only  be  founded 
on  the  notion  of  function.  This  is  the  prin- 
ciple which  has  already  aided  me  in  estab- 
lishing a  general  classification  of  glands, 
in  1893.76 

There  will  be  remarked  in  the  double 
classification  that  I  present  (see  pp.  172- 
174)  quite  numerous  gaps;  these  are  the 
blanks  in  our  actual  knowledge.  Thus,  as  yet 
we  know  neither  the  active  substance  manu- 
factured by  the  thyroid  and  parathyroids, 
nor  that  produced  by  the  interstitial  gland 
of  the  testicle,  nor  that  which  the  corpora 
lutea  produce ;  we  do  not  know  what  is  the 
principle    formed    in    the    thyroid   which 

78  E.  Gley,  ' '  Conception  et  classification  des  glandes ' ' 
(Revue  scientifique,  July  1,  1893,  LII,  p.  8).  Cf.  also 
"Essais  de  philosophic  et  d'histoire  de  la  biologie,"  by 
E.  Gley,  Paris,  Masson  and  Co.,  1900,  p.  123-160. 


170    THE  INTERNAL  SECRETIONS 

manifests  so  powerful  a  morphogenetic  ac- 
tion; we  are  likewise  ignorant  concerning 
the  substances  of  pituitary  and  thymic 
origin,  since  no  one  has  even  attempted — 
which  is  partially  explained  by  the  diffi- 
culties in  technics — to  search  for  them  in 
the  venous  blood  of  the  hypophysis  and 
thymus.  And  lacking  as  we  do  this  funda- 
mental proof,  we  do  not  possess  either  for 
one  or  the  other  of  these  organs,  any  evi- 
dence that  the  symptoms  produced  by  ex- 
tensive disease  or  complete  extirpation  of 
either  organ  may  be  greatly  ameliorated 
or  cured  by  the  administration  of  the  ex- 
tract of  the  affected  organ.  In  other 
words,  there  is  no  proof  by  "substitution 
therapy ' '  (Substitutionstherapie) . 

The  reader  will  also  note  the  question 
marks  in  the  table.  Do  we  know,  for  ex- 
ample, the  nature  and  mode  of  action  of 
that  product  of  the  pancreas  which  plays 
so  important  a  part  in  the  regulation  of 
glycemia?     Are  we  sure  that  iodothyro- 


CHARACTERISTICS  OF  GLANDS   171 

globulin  is  the  cause  of  the  excitatory  ac- 
tion of  the  thyroid  secretion  on  the  nitrog- 
enous and  respiratory  exchanges?  Like- 
wise, it  is  not  as  yet  certain  that  the  para- 
thyroids act  by  an  antitoxic  mechanism; 
and  we  do  not  know  positively,  in  spite  of 
the  researches  of  Ancel  and  Bouin,  Lane- 
Claypon,  and  Starling,  the  organ  which 
supplies  the  blood  with  the  substance 
whose  action  establishes  the  secretion  of 
milk.  Furthermore,  we  are  not  sure,  in 
spite  of  all  that  has  been  written  on  the 
subject,  that  there  is  true  suprarenal  in- 
sufficiency of  a  functional  nature. 

Whatever  these  considerations  may  be,  it 
has  appeared  to  me  to  be  possible,  from 
the  physiological  point  of  view  and  by  con- 
stant criticism  made  from  this  point  of 
view  of  the  knowledge  really  acquired,  to 
establish  a  classification  of  the  endocrine 
glands  and  the  products  in  the  two  follow- 
ing tables. 


I.    Table  op  Internal  Secretory  Glands,  Giving  the 

Depending  on  Them,  and  the  Diseases  or 

Alteration  of  These  Organs 


Organ 

Products  Secreted 

I. 

Nutritive 
Glands 
(taking 
part  in         _, 
transforma- 
tion of 

1. 

Substances 
taking  part 
in  nutrition 

2. 

Excretory 
products 

3. 

Substances 
taking  part 
in  morpho- 
,  genesis 

'  Glands  of  the  in- 
testinal    mucous 

I 

Liver 

[  Parathyroids 

"Interstitial  gland 
of  the  testicle  and 
corpus  luteum. . . 

\  Thyroid 

Hypophysis 

[  Fatty  bodies .... 
\  Albumins  of  the 
I  blood  (?) 

f  Diastase  (?)  parti- 
j  cipating  in  glyco- 
[  genesis  or  glycolysis 

f  Urea;  phenylsul- 

matter) 
and  elabo- 
ration of — 

1 

J 

II. 

Glands  servi 
the  composi 
ternal  mediu 

ng  to  maintain 
Aon  of  the  in- 

[  Choroid  plexuses. 

Antithrombine . . 

III. 

Glands   which   regulate   or 

Glands  of  the  duo- 
deno-jejunal  mu- 
cous membrane. . 

Myometrial 
gland,  or  placen- 
ta, or  fetus  (?) .  . 

Thyroid 

1  A     galactogogue 

f  A  substance  which 
J  excites  katabolisrn 
)  (iodo-thyroglobu- 
(  Un?) 

Organs  participating  in  nu- 

Non-glandular 
[  Fatty  bodies .... 

ORGANS  BUT  WHICH 

Fat 

trition  or  morphogenesis . . . 

172 


Products   Secreted,  the   Functional  Correlations 
Disorders  Resulting  from  the  Inhibition  or 
and   Their  Secretions 


Physiological  Role  of 
Products  Secreted 


Correlations  Between 


Diseases 


Production  of  energy- 
Plastic  rdle 

Production  of  energy 
Plastic  r&le 

Formation  of  glyco- 
gen or  destruction  of 
sugar 

Mobilization  of  sugar 

'  Transformation   of 
toxic   products   into 
non-toxic    (antitoxic 

[  function  of  the  liver) 

Antitoxic  function  (?) 


I  Development  of  the 
genital  tract  and  of 
the  accessory  genitnl 
glands,  development 
of  the  skeleton 

(Development  of  the 
skeleton 
nervous  system 
germinal  gland 

f  Development  of  the 
1  skeleton 


Intestine  and  tissues 

Liver  and  muscles. . 
Liver  and  blood 

Pancreas  and  liver. 

Adrenals  and  liver. 

Liver  and  kidneys 


f  Thyroid  and  Para- 
\  thyroids 

Interstitial  gland  or 
corpus  luteum  and 
accessory  genital 
glands,  interstitial 
gland  &  osseous  tissue 

Thyroid  and  osseous 

tissue 
Thyroid  and  brain 
Thyroid    and     tes- 
ticles or  ovaries 

Hypophysis  and  os- 
seous tissue 


Diabetes  through  he- 
patic hypersecretion 
of  sugar 


Diabetes  throogh  sup- 
pression of  pancre- 
atic action 

Glycosuria  through 
.  hyperadrenalinemia 


Tetany  through  sup- 
pression of  function 


Infantilism  of  testic- 
ular origin 


Arrest  of  develop- 
ment, cretinism,  myx- 
edematous condi- 
tions 


Acromegaly 


/  Coagulability  of  the 

\  blood 

I  Physical  role  known 
\  Eliminative  rdle  (?) 


Liver  and  blood . , 


Hemophilia  through 
an  excess  of  anti- 
thrombine 


Pancreatic  secretion 


f  Functions  of  the 
I  sympathetic  nervous 
{ system 


•  Secretion  of  milk . 


(Nitrogenous  and  res- 
piratory exchanges. . 


f  Stomach,  duodenum 
\  and  pancreas 

Adrenals  and  sym- 
pathetic nervous  sys- 
tem   

Uterus,  placenta  or 
fetal  organs,  and 
breasts 

Thyroid  and  tissues 
in  general 


Addison's  disease. 
Suprarenal  insuffi- 
ciency (?) 


Inhibition  of  nutri- 
tion because  of  lack 
of  thyroid  secretion 


FUNCTION     AS     ENDOCRINE    GLANDS 

Production  of  energy 
Activation  of  trypsin 
Development  of  the 
skeleton 


Spleen  and  pancreas 
Thymus  and  os- 
seous tissue 


173 


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THE   FUNCTION   OF  THE   INTERNAL   SECRETOEY 
GLANDS 


ni 


THE   FUNCTION   OF   THE   INTERNAL  SECRETORY 
GLANDS 

The  normal  and  the  pathological  activi- 
ties may  be  considered  separately.  From 
this  second  point  of  view  we  are  con- 
fronted by  the  pathological  problems  which 
are  of  the  principal  importance  at  present. 

I.      THE   NORMAL   ACTIVITIES 

We  are  first  called  upon  to  answer  two 
questions,  the  first  of  a  chemical  nature 
and  the  second  physiological.  The  first  is 
to  learn  out  of  which  materials  the  glandu- 
lar elements  manufacture  the  specific  sub- 
stances which  they  secrete;  or,  in  other 
words,  where  they  obtain  the  substances 
which  they  use  in  the  production  of  the 
specific  secretions;  and  the  second  is  to 

177 


178    THE  INTERNAL  SECRETIONS 

learn  the  causes  which  provoke  cellular 
excretion,  or  the  discharge  of  the  gland. 
The  influence  of  the  nervous  system  on  the 
internal  secretions  is  then  to  be  consid- 
ered, and  finally  that  of  the  reciprocal  ac- 
tions of  these  secretions  and  their  prod- 
ucts. On  this  last  point  rest  important 
pathological  problems. 

1.  The  first  question,  that  of  the  forma- 
tion of  specific  products,  has  been  well 
studied  for  the  glands  which  elaborate  and 
discharge  into  the  blood  nutritive  ma- 
terials. We  are  acquainted  with  a  consid- 
erable number  of  influences  which  cause 
an  increase  in  the  quantity  of  hepatic  gly- 
cogen, that  is  to  say,  of  the  substance  from 
which  comes  the  glycose  of  the  blood. 
Similarly,  the  liver,  which  receives  much 
of  ammonia  salts,  produces  much  urea.  It 
has  been  known  for  a  long  time  that  the 
excessive  ingestion  of  fats  causes  an  in- 
crease in  the  fat  deposits  which  are  seen  in 
adipose  subjects. 


FUNCTION  OF  THE  GLANDS     179 

We  have  little  evidence  about  the  other 
categories  of  endocrine  glands.  In  the 
case  of  the  production  of  substances  hav- 
ing a  trophic  function,  the  little  that  we 
know  concerns  the  thyroid.  It  has  been 
stated  that  the  administration  of  foods  rich 
in  iodin,  or  of  iodid  preparations,  causes 
an  increase  of  the  iodin  present  in  the  thy- 
roid. Confirmation  of  the  first  experi- 
ments of  Baumann  is  still  awaited. 

In  the  case  of  the  suprarenal  glands,  it 
has  been  thought  (Battelli,  1903)  that  the 
substances  formed  in  muscle  during  ac- 
tivity or  in  the  central  nervous  system  en- 
gender a  "proadrenalin." 

2.  No  further  progress  has  been  made 
in  studying  the  question  of  the  glandular 
excitants.  Quite  a  large  number  of  sub- 
stances are  known  which  cause  the  passage 
of  antithrombin  in  the  blood  of  the  hepatic 
vein.  As  an  example  we  may  take  the  in- 
fluence of  the  albumoses,  which  has  been 
thoroughly  studied.    It  is  known  with  the 


180    THE  INTERNAL  SECRETIONS 

highest  degree  of  certainty  that  secretin  is 
discharged  into  the  blood  after  contact  of 
acids  or  soaps  with  the  duodenojejunal 
mucous  membrane.  But  do  these  sub- 
stances cause  its  formation  from  a  "pro- 
secretin, ' '  which  had  previously  existed  in 
the  mucous  membrane,  or  do  they  merely 
liberate  the  secretin,  already  completely 
formed?  In  the  case  of  the  suprarenal  se- 
cretion, Tscheboksaroff  has  observed  in  the 
laboratory  of  Mislavsky  that  an  injection 
of  physostigmin  increases  the  amount  of 
adrenalin  which  is  discharged  into  the  cap- 
sular vein  (experiments  on  dogs,  1910) ; 
pilocarpin  has  not  this  effect.  Finally, 
histological  observations  have  shown  that 
pilocarpin  causes  swelling  of  the  thyroid, 
and  the  collection  of  colloid  matter  in  the 
vesicles,  this  then  spreading  into  the  in- 
tervesicular  lymphatic  spaces ;  the  same  is 
true  after  ligature  of  the  common  duct  (K. 
Hiirthle,  1894).  Hence  we  may  suppose 
that  the  bile  excites  thyroid  secretion. 


FUNCTION  OF  THE  GLANDS     181 

Undoubtedly,  other  facts  might  be  added 
to  these.  They  are,  however,  too  uncertain 
for  us  to  be  able  to  consider  them  as  dem- 
onstrated without  the  most  rigorous  veri- 
fication. Thus,  it  has  been  stated  that 
when  an  organic  extract  is  introduced  into 
the  body,  it  tends  towards  the  homologous 
organ,  hypertrophies  and  stimulates  it. 
Homo  stimulants  have  even  been  spoken  of. 
Contradiction  notwithstanding,  it  has  even 
been  maintained  that  these  extracts,  when 
administered  in  small  doses,  moderate  the 
function  of  the  homologous  organ.  In 
such  a  manner  is  the  practise  of  organo- 
therapy justified  by  its  supporters,  in  spite 
of  the  contradictions  constantly  being  en- 
countered. 

3.  The  influence  of  the  nervous  system 
on  the  internal  secretions  has  been  demon- 
strated in  the  cases  of  the  glycogenic  func- 
tion of  the  liver  and  the  passage  of  adrena- 
lin into  the  blood.  The  evidence  in  the  case 
of  the  liver  is  found  in  all  treatises  on 


182    THE  INTEENAL  SECRETIONS 

physiology.  The  proofs  for  the  second  are 
given  largely  in  Biedl's  book  and  Swale 
Vincent's  study,  already  mentioned,  as 
well  as  in  a  remarkable  study  by  G.  Bayer  x 
[and  in  more  recent  works  of  Crile,  Can- 
non and  others — Ed.] .  Finally,  it  has  been 
thought  possible  to  prove  directly  the  ac- 
tion of  the  nervous  system  on  the  thyroid 
by  showing  that  stimulation  of  the  laryn- 
geal nerves  (L.  Ascher  and  M.  Flack,  1910) 
increases  the  excitability  of  the  depressor ; 
it  being  admitted,  following  the  researches 
of  E.  de  Cyon,  that  the  latter  is  dependent 
on  the  thyroid  secretion. 

4.  The  reciprocal  glandular  actions,  or 
humoral  interrelations,  belong  to  the  group 
of  phenomena  termed  as  functional  hu- 
moral correlations.  But  all  correlations  of 
this  sort,  which  are  determined  and  char- 
acterized by  the  action  of  an  internal  secre- 

1 G.  Bayer,  ' '  Die  normale  und  pathol.  Physiologie 
des  chromaffinen  Gewebes  der  Nebennieren"  {Ergebnisse 
der  pathol.  Anat.,  1910,  XIV,  132). 


FUNCTION  OF  THE  GLANDS     183 

tory  product  on  an  organ  of  the  same  an- 
atomical system  or  of  a  distinct  and  more 
or  less  distant  system,  are  not  interrela- 
tions. The  latter  are  characterized  by  the 
reciprocal  action  of  two  products  of  inter- 
nal secretion. 

Undoubtedly,  confusion  between  these 
two  notions  tends  to  exist.  To  avoid  this, 
however,  it  would  suffice  to  use  a  little 
criticism  and  consider  some  fundamental 
facts  in  the  history  of  internal  secretions. 
If  secretin,  for  example,  is  the  specific  ex- 
citant of  pancreatic  secretion,  does  the 
pancreas  furnish  a  product  of  internal  se- 
cretion acting  on  the  intestinal  secretion? 
And  where,  therefore,  is  the  reciprocal 
connection  between  the  pancreatic  sub- 
stance which  acts  on  the  liver,  the  organ  in 
which  the  metabolism  of  the  carbohydrates 
occurs,  and  a  substance  of  hepatic  origin? 
The  demonstration  which  follows  shows 
how  important,  it  is  to  maintain  the  distinc- 


184    THE  INTERNAL  SECRETIONS 

tion  between  functional  humoral  correla- 
tions and  humoral  interrelations. 

How  has  the  latter  theory  become  so 
widely  accepted?  It  has  been  admitted 
that  there  is  no  endocrine  gland  which  has 
no  mutual  connections  with  one  or  several 
others,  either  of  excitation  or  of  recipro- 
cal antagonism.  Let  us  now  reproduce  the 
diagram  of  the  promoters  of  the  theory, 
the  Viennese  pathologists,  Eppinger,  Falta 
and  Rudinger  (1908),2  which  sums  up  the 
principle  of  these  actions. 

From  this  diagram  it  is  seen  that  the  thy- 
roid secretion  is  the  excitant  of  the  supra- 
renal apparatus,  and  adrenalin  the  excitant 
of  the  thyroid.  Furthermore,  adrenalin 
exercises   an  inhibitory  influence   on  the 

2  H.  Eppinger,  W.  Falta  and  C.  Eudinger,  ' '  tiber  der 
Wechselwirkungen  der  Driisen  mit  innerer  Sekretion" 
(Zeitschr.  fiir  Urn.  Med.,  1908  and  1909,  LXVI,  152, 
and  LXVIII,  380)  ;  W.  Falta,  "tiber  der  Korrelationen 
der  Driisen  mit  innerer  Sekretion"  (Lewin's  Ergebnisse 
der  Wissenschaftliche  Med.,  1909,  I,  108-118).  Cf.  also 
Caro,  ' '  Wechselwirkung  der  Organen  mit  innerer  Sekre- 
tion" {Media.  Klinilc,  January  23,  1910,  VI,  136-139). 


FUNCTION  OF  THE  GLANDS     185 

pancreas,  and  the  secretion  of  the  latter 
has  the  same  influence  on  the  adrenals. 
Also,  the  thyroid  secretion  moderates  the 
activity  of  the  pancreas  and  the  internal 
pancreatic  secretion  holds  the  activity  of 
the  thyroid  within  bounds.    Assuming,  for 

Thyroid 


Insular  Apparatus 
of  the  Pancreas 


Chromaffin  System 


Inhibitory  Action 


example,  hypoactivity  or  suppression  of 
the  activity  of  the  thyroid  and  there  will 
result  hyperfunction  of  the  pancreas  re- 
sulting from  the  disappearance  of  the  nor- 
mal restraining  action  of  the  former  gland 
upon  the  latter;  likewise  a  diminution  in 
the  function  of  the  adrenals  occurs.  Let 
there  be  given,  on  the  other  hand,  hyper- 


186    THE  INTERNAL  SECRETIONS 

activity,  from  some  morbid  influence,  of 
the  thyroid.  The  restraining  action  of  the 
pancreas  will  be  exercised  more  energetic- 
ally and  there  will  result  a  more  or  less 
marked  insufficiency  of  the  functions  of 
the  latter  gland,  and  at  the  same  time 
hyperfunction  of  the  chromaffin  system. 

Analogous  connections  have  been  inves- 
tigated as  regards  the  functional  activity 
of  other  endocrine  organs  and  their  au- 
thenticity established.  This  is  the  case 
with  the  ovary,  thyroid  and  pituitary 
body ;  the  adrenals  and  genital  glands,  etc. 
Isaac  Ott,  for  example,  maintains  that  the 
anterior  lobe  of  the  pituitary  body  has  an 
inhibitory  action  on  the  genital  glands,  the 
testicles  and  ovaries,  and,  reciprocally, 
that  the  latter  have  a  like  action  on  the 
hypophysis.  He  also  says  that  the  thyroid 
and  pituitary  are  mutually  compensatory.3 

Such  are  the  efforts  that  have  been  made 

8  Isaac  Ott,  ' '  Internal  Secretions  from  a  Physiological 
and  Therapeutical  Standpoint,"  Phil.,  1910;  see  p.  125. 


FUNCTION  OF  THE  GLANDS     187 

to  generalize  the  conception  of  humoral 
interrelations. 

Both  parts  of  the  vegetative  nervous 
system  share  in  these  reciprocal  actions. 
They  are  the  autonomous  and  the  sympa- 
thetic systems.  It  is  known,  for  example, 
that  the  product  of  the  adrenal  secretion 
is  the  excitant  of  the  sympathetic  nervous 
system.  We  might  therefore  say  that 
adrenalin  is  sympathicotropic,  and  the 
product  of  the  thyroid  secretion,  which 
acts  on  the  tone  of  the  vagus  (F.  Kraus, 
1908),  is  vagotropic,  or,  better,  autonomo- 
tropic.  Thus  adrenalin  produces  the  same 
effects  as  a  stimulant  of  the  sympathetic 
system;  whenever  it  encounters  a  motor 
fiber  of  this  system,  it  produces  a  motor 
effect ;  if  it  strikes  an  inhibitory  fiber  of  the 
same  system,  the  effect  is  of  an  inhibitory 
character.  But  there  are  some  organs 
which  possess  a  double  enervation,  auton- 
omous and  sympathetic.     In  this  case,  as 


188    THE  INTERNAL  SECRETIONS 

has  been  well  said  by  G.  Fano,4  these  or- 
gans "possono  reagire  a  sostanze  iniettate 
dall'esterno  o  elaborate  dalP  organismo 
ragginngondo  effetti  molto  notevoli  perche 
a  quelle  stimolazioni  tossiche  possono 
risponderi  non  solo  liberando  le  determi- 
nant! d'una  funzione  ma  pure  contempor- 
aneamente  inibendo  quelle  condizioni  an- 
tagonistic!^ che  si  opporrebbero  alia  sua 
facile  e  completa  attuazione."  The  first 
question  to  be  discussed  is  if  all  the  actions 
started  by  endocrine  products  are  the  re- 
sults of  the  stimulation  or  inhibition  of 
sympathetic  or  autonomic  nerve  fibers. 
It  is  evident  that  we  may  say,  for  example, 
that  the  action  by  which  glycogen  is  col- 
lected in  the  liver  is  regulated  by  the  sym- 
pathetic, and  that  the  internal  secretion  of 
the  pancreas  is  regulated  by  the  vagus. 
But  there  is  no  proof  that  these  secretions 
cannot  take  place  under  purely  humoral 
influences,  and  there  are  proofs  that  the 

*  Loo.   cit. 


FUNCTION  OF  THE  GLANDS     189 

mobilization  of  sugar  in  the  liver  in  the 
form  of  glycogen  and  the  accumulation  of 
the  latter  are  diastatic  phenomena.  Like- 
wise, the  formation  of  fibrinogen  in  the 
liver,  and  of  antithrombin  in  the  same 
gland,  take  place  independently  of  the 
nervous  system.  And  it  would  be  easy  to 
cite  other  instances  of  the  same  nature. 

It  is  no  less  important  to  discuss  another 
question  which  concerns  the  connections 
between  the  vegetative  nervous  system  and 
reciprocal  glandular  activities.  We  have 
been  led  to  admit  (Eppinger  and  Hess, 
1909-1910)  that  a  certain  rise  in  the  nor- 
mal tone  of  the  pneumogastric  (constitu- 
tional vagotonia)  or  of  the  sympathetic 
(sympathicotonia)  may  be  observed  in 
various  subjects.  Hypertonia  of  the  vagus 
nerves,  i.  e.,  vagotonia,  is  caused  by  the 
excessive  secretion  of  autonomotropic  hor- 
mones accompanied  by  a  deficient  secretion 
of  sympathicotropic  hormones.  This  is  a 
constitutional  anomaly  and  quite  a  variety 


190    THE  INTEENAL  SECEETIONS 

of  disorders  may  arise  from  it.  The  vic- 
tims of  this  anomaly  show  a  particular 
sensibility  to  autonomotropic  poisons,  like 
atropin  and  pilocarpin,  and  a  lesser  sen- 
sibility to  sympathicotropic  poisons,  as 
adrenalin.  The  reverse  is  true  in  sympa- 
thicotonia, which  furnishes  us  with  a  com- 
plete series  of  diagnostic  signs. 

But  the  proofs  of  the  existence,  and  a 
fortiori  of  the  action,  of  autonomotropic 
(thymicolymphatic  and  pancreatic)  hor- 
mones are  altogether  insufficient.  Is  there 
a  physiologist  who  has  actually  recognized 
a  hormone  in  a  thymus  extract,  in  the  sense 
that  the  word  hormone  should  be  used  (see 
p.  136)  ?  The  theory  is  therefore  based  on 
an  unstable  foundation.  Furthermore,  the 
facts  on  which  it  rests  are  either  uncertain 
or  altogether  inexact  and  the  pharmaco- 
dynamic criterion  to  which  has  been  at- 
tributed so  high  a  diagnostic  value  is  far 
from  being  infallible.  Some  most  useful 
points  on  these  various  questions  will  be 


FUNCTION  OF  THE  GLANDS     191 

found  in  several  recent  studies.5  In  any 
case,  the  question  if  nervous  actions  par- 
ticipate in  reciprocal  glandular  activities, 
and  to  what  degree  this  occurs,  is  as  yet  far 
from  solved. 

However,  it  is  of  importance  to  examine 
the  theory  of  humoral  interrelations  in  it- 
self, and  we  shall  do  this  immediately. 

What  are  the  facts  on  which  it  is  based? 
They  are  anatomo-pathological  data,  clini- 
cal observations  and  some  animal  experi- 
ments. At  the  bedside  we  analyze  a  syn- 
drome in  which  disorders  depending  on  the 
alteration  of  an  endocrine  gland  appear  to 
predominate.    At  the  autopsy  we  actually 

SK.  Peteen  und  I.  Thorling,  "Unters.  iiber  das 
Vorkommen  von  'Vagotonus  und  Sympathicotonus '  " 
(Zeitschrift  fur  Tclin.  Med.,  1911,  LXXIII,  27-46);  J. 
Bauer,  ' '  Zur  Funktionspriif ung  des  vegetativen  Nerven- 
systems"  (BeutscTies  Arch,  fur  Tclin.  Med.,  1912,  CVII, 
39);  P.  Fleischmann,  "tiber  die  Wechselbeziehungen 
der  Driisen  mit  innerer  Sekretion"  (Med.  Klinilc,  Feb.  4, 
1912,  p.  177);  N.  Pende,  "Sulla  vagotonia  constituzion- 
ale  e  morbosa  di  Eppinger  ed  Hess  e  su  alcuni  recenti 
metodi  d'indagine  semiologica  del  sistema  nervoso  sim- 
patieo"  (II  Tommasi,  April  30,  1912,  VII,  265). 


192    THE  INTERNAL  SECRETIONS 

find  this  change,  but,  besides,  there  are  dis- 
covered lesions  of  other  endocrine  glands 
by  which  it  is  believed  possible  to  explain 
disorders  which  were  not  accounted  for  by 
the  lesion  of  the  organ  primarily  attacked. 
By  combining  clinical  facts  and  post  mor- 
tem observations,  a  connection  between  the 
various  organs  studied  is  finally  arrived 
at.  The  question  is,  What  is  the  nature 
of  this  connection?  Are  we  dealing  with 
a  synergic,  reciprocal  relation,  like  that 
maintained  by  Eppinger,  Falta  and  Rudin- 
ger !  Or  have  we  simply  concomitant  phe- 
nomena, provoked  by  the  same  cause  acting 
on  divers  organs? 

The  second  notion,  which  results  solely 
from  the  consideration  of  clinical  facts,  has 
given  rise  to  the  establishment  of  syn- 
dromes of  pluriglandular  insufficiency, 
due  to  several  French  pathologists  (H. 
Claude,  1907-1908;  L.  Renon,  1908;  L.  Re- 
non  and  Arthur  Delille,  1908,  etc.).  The 
conception  of  these  syndromes  has  led  to 


FUNCTION  OF  THE  GLANDS     193 

associative  opotherapy,  the  simultaneous 
administration  of  several  organic  extracts 
(L.  Benon,  1908),  which  has  been  much 
vaunted.  However,  the  anatomo-patho- 
logical  method  is  subject  to  errors  of 
interpretation.  The  statement  concern- 
ing lesions  in  various  organs  does  not 
prove  that  there  normally  exists  any  as- 
sociation whatsoever  between  these  or- 
gans. There  have  been  found  lesions  of 
the  testicles  in  individuals  affected  with 
cirrhosis  of  the  liver,  and  likewise  follow- 
ing resection  of  the  liver  or  ligature  of 
the  bile  duct.  Has  any  one,  therefore, 
drawn  the  conclusion  that  there  is  a  re- 
lation between  the  bile  duct  and  the 
testicles  ?  Is  it  probable  that  the  retention 
of  toxic  substances,  following  lesions  of 
the  liver,  causes  parenchymatous  altera- 
tions here  and  there,  but  more  markedly 
in  the  testicles  ?  Similarly,  are  we  justified 
in  maintaining  that  the  lesions  found  in  a 
number  of  organs  of  thyroidectomized  ani- 


194    THE  INTERNAL  SECRETIONS 

mals  are  directly  due  to  the  loss  of  the  thy- 
roid function  1  Are  they  not  rather  one  of 
the  effects  of  the  intoxication  and  meta- 
bolic disorders  which  occur  in  these  ani- 
mals? 

The  tendency  at  present  to  consider  the 
study  of  hormones  as  being  nothing  else 
than  the  investigation  of  reciprocal  ac- 
tions, or  humoral  interrelations  is  there- 
fore little  justified.  If,  as  I  have  already 
said,6  interrelations  enter  into  the  group 
of  functional  humoral  correlations,  it  is 
necessary  that  all  the  latter  be  interrela- 
tions. This  is  what  is  shown  by  the  actual 
facts. 

Reciprocal  Relations  between  the 
Pancreas  and  the  Adrenals. — Let  us  con- 
sider the  reciprocally  antagonistic  rela- 
tions admitted  to  exist  between  the  pan- 
creas and  the  adrenals.     In  favor  of  the 

•E.  Glet,  "Correlations  fonctionelles  et  inter-rela- 
tions humoraleB ' '  (Bev.  ge"n6rale  des  sciences,  July  30, 
1913,  p.  537). 


FUNCTION  OF  THE  GLANDS     195 

idea  of  an  inhibitory  action  of  the  pan- 
creas upon  the  adrenals,  it  has  been  main- 
tained that  following  the  suppression  of 
the  former  organ  the  action  of  adrenalin 
is  more  marked.  The  following  was  ob- 
served by  0.  Loewi:7  He  removed  the 
pancreas  and  then  noticed  that  the  ad- 
ministration of  adrenalin  was  followed 
by  dilatation  of  the  pupil,  which  does 
not  occur  in  a  normal  animal.  Loewi  ob- 
served in  ten  out  of  eighteen  diabetics  a 
marked  dilatation  of  the  pupil  following 
the  administration  of  adrenalin,  while  in 
thirty  healthy  subjects  this  phenomenon 
was  noted  but  twice.  To  explain  this  ef- 
fect it  is  suggested  that  the  pancreas  se- 
cretes a  substance  antagonistic  to  adrena- 
lin. The  latter  acts  on  the  pupil  through 
the  intermediary  of  the  sympathetic.  The 
antagonistic  substance  inhibits  the  sympa- 

7  O.  Loewi,  ' '  Eine  neue  Funktion  des  Pankreas  unci 
ihre  Beziehung  zum  diabetes  mellitus"  (Wiener  Min. 
Woch.,  1907,  p.  747). 


196    THE  INTERNAL  SECRETIONS 

thetic  or  stimulates  the  constrictor,  so  that 
when  the  pancreas  is  destroyed  this  action 
can  no  longer  be  exercised  and  the  adrena- 
lin is  free  to  produce  its  full  effects. 

These  observations  of  Loewi  are  cer- 
tainly exact.  Is  the  interpretation  correct? 
In  this  connection  we  should  mention  that 
Bittorf 8  (1911)  carried  out  Meltzer's  re- 
action with  the  blood  serum  of  ten  dia- 
betics and  in  no  case  did  he  find  an  aug- 
mentation in  the  quantity  of  adrenalin  in 
the  blood.  Furthermore,  in  diabetic  ani- 
mals and  in  man,  permanent  dilatation  of 
the  pupil  has  never  been  observed.  But 
why  not  decide  the  question  on  a  surer  and 
more  solid  basis — that  of  direct  experi- 
ence? Has  any  one  found  an  increase  in 
the  proportion  of  adrenalin  in  the  supra- 
renal blood  of  depancreatized  animals'? 
The   experiment   has   not   even   been   at- 

8  A.  Bittorf,  "1st  beim  Diabetes  Mellitus  eine  Ueber- 
fonktion  der  Nebennieren  nachweisbar?"  (Mimchencr 
med.  Woch.,  1911,  No.  42). 


FUNCTION  OF  THE  GLANDS    197 

tempted  as  yet.    Researches  on  this  point 
have  been  begun  in  my  laboratory. 

It  has  been  maintained  that  the  supra- 
renal capsules  have  a  reciprocally  inhibi- 
tory action  on  the  function  of  the  pancreas. 
The  following  is  the  experiment  performed 
by  R.  Pemberton  and  J.  E.  Sweet  (1908, 
1910),  according  to  whom  this  action  is 
even  manifested  on  the  external  pancreatic 
secretions:  A  preliminary  injection  of 
adrenalin  prevented  the  action  of  secretin. 
This  antagonism  of  the  two  \  substances 
was  not  found  by  Gley  (1911). 9  Ziilzer10 
observed  glycosuria  following  the  extirpa- 
tion of  the  pancreas  cease  after  ablation 
of  the  two   suprarenals.     Also,  Frouin11 

9  When  an  antagonism  is  stated  to  occur,  it  is  due  to 
the  temporary  anemia  of  the  pancreas,  resulting  from 
the  vasoconstriction  produced  by  the  adrenalin  (Willis 
Edmunds,  1910;  Wertheimer,  1911;   Gley,  1911). 

10  G.  ZtJlzer,  M.  Dohrn,  and  A.  Maexer,  ' '  Neuere  Un- 
ters.  iiber  den  experimentellen  Diabetes"  (Deutsch. 
med.  Woch.,  1908,  p.  1380). 

"A.  Frouin,  "Ablation  des  capsules  surrenales  et 
diabete  pancr^atique ' '  (C.  B.  de  la  Soc.  de  biol.,  Feb.  8, 
1908,  LXIV,  p.  216). 


198    THE  INTERNAL  SECRETIONS 

has  published  the  results  of  two  analo- 
gous experiments  in  which  pancreatic  dia- 
betes in  a  dog  was  diminished  after  the 
ablation  of  one  suprarenal  capsule  and  two- 
thirds  of  the  other.  But  Ziilzer  's  dogs  only 
survived  twenty-four  to  thirty-six  hours. 
Under  these  conditions,  what  does  a  dimi- 
nution in  the  elimination  of  sugar  signify1? 
Is  it  not  a  well  known  fact  that  in  animals 
suffering  from  malnutrition,  cachectic  ani- 
mals or  those  near  death,  diabetes  is  at- 
tenuated or  may  even  disappear?  We 
should  not  forget  the  somewhat  paradoxi- 
cal but  just  expression  of  Claude  Bernard 
that  "in  order  to  be  diabetic,  one  must 
look  well."  Now,  decapsulated  animals 
are  in  a  state  of  organic  decay.  The  recent 
experiments  of  Athanasiu  and  his  pupil 
Gradinesco  12  have,  moreover,  shown  that 

13  Cf.  J.  Athanasiu  and  Gradinesco,  "Les  capsules 
surrenales  et  les  eehanges  entre  le  sang  et  les  tissus ' ' 
(C.  B.,  August  9,  1909),  and  A.  V.  Gradinesco,  "Der 
Einfluss  der  Nebennieren  auf  den  Blutkreislauf  und 
den  Stoffwechsel"  (Arch.  f.  die  ges.  Physiol.,  1913, 
CLII,  pp.  187-253). 


FUNCTION  OF  THE  GLANDS     199 

adrenalin,  by  the  tonic  influence  that  it  ex- 
erts on  the  endothelium  of  the  blood  capil- 
laries, regulates  the  material  exchanges  be- 
tween the  blood  and  the  interstitial  plasma 
of  the  tissues,  so  that  if  the  secretion  of 
this  product  is  abolished  these  exchanges 
are  put  in  a  state  of  profound  disorder 
and  their  reduction  appears  to  be  the  cause 
of  death  following  ablation  of  the  adrenals. 
It  would  therefore  seem  that  one  passes 
by  the  facts  too  boldly  when  he  maintains 
that  there  exists — alongside  of  a  "  posi- 
tive adrenal  diabetes,"  due  to  a  hyperac- 
tivity of  the  suprarenal  glands  which  pro- 
duce more  adrenalin,  leading,  under  the  in- 
fluence of  this  substance,  to  hyperglycemia 
and    glycosuria — a    "negative    diabetes," 
from  the  suppression  of  the  permanently 
moderating  influence  exercised  by  the  pan- 
creas on  the  suprarenal  capsules,  and  that 
in  the  classic  pancreatic  diabetic  (J.  von 
Mering  and  Minkowski,  Lancereaux),  this 


200    THE  INTERNAL  SECRETIONS 

last  factor  plays  its  role.  Following  the 
destruction  of  the  pancreas,  adrenalin 
would  be  secreted  in  excess  and  thus  the 
pancreatic  diabetic  would  in  reality  be  an 
adrenalin  diabetic  (Ziilzer).  As  G.  Bay- 
er 13  justly  remarks,  the  physiological  an- 
tagonism between  the  two  glands  and  the 
fact  of  the  hyperactivity  of  the  chromaffin 
system  after  extirpation  of  the  pancreas 
could  only  be  accepted  if  there  were  found : 
(a)  Histological  signs  of  increased  func- 
tion in  the  suprarenal  glands  of  depan- 
creatized  animals ;  (b)  abnormal  quantities 
of  adrenalin  in  the  blood  of  depancreatized 
animals  and  diabetic  human  beings ;  (c)  in 
the  same  animals  signs  of  hyperactivity  of 
the  chromaffin  system,  as  elevation  in  the 
arterial  pressure.  Such  a  demonstration 
has  not  as  yet  been  furnished.  The  facts 
amassed  by  Viennese  pathologists  only 
show  that  the  loss  of  the  pancreas  has, 
under  certain  conditions,  the  same  effect 

uLoo.  tit. 


FUNCTION  OF  THE  GLANDS    201 

as  excitation  of  the  adrenals,  that  is,  in- 
creased secretion  of  adrenalin.  Thus  the 
result  is  the  same  as  after  section  of  the 
inhibitory  nerves  of  the  heart  or  stimula- 
tion of  the  accelerating  nerves.  Section 
of  the  vagus  does  not  provoke  acceleration 
of  the  heart  beat  because  increased  activity 
of  the  sympathetic  follows,  but  because  the 
normal  inhibitory  influence  is  suppressed. 
Likewise,  the  pancreas  and  the  suprarenals 
act  oppo  singly  on  the  accumulation  of 
sugar.  That  does  not  prove  that  the  ac- 
tion of  one  is  determined  by  the  suppres- 
sion of  the  action  of  the  other,  and  con- 
versely. 

Reciprocal  Relations  between  the 
Thyroid  and  the  Adrenals. — Is  it  very 
well  established  that  the  thyroid  and 
adrenals  exert  reciprocal  stimulation  on 
one  another?  According  to  the  experi- 
ments of  Eppinger,  Falta  and  Rudinger,14 
adrenalin  no  longer  causes  glycosuria  in 

uLoc.  tit.,  1908. 


202    THE  INTEBNAL  SECEETIONS 

thyroidectomized  animals;15  if  these  ani- 
mals be  administered  thyroid  prepara- 
tions the  action  of  adrenalin  is  reestab- 
lished.16 From  this  there  follows  im- 
mediately the  explanation  of  the  glyco- 
suria observed  very  frequently  in  exoph- 
thalmic goiter;  in  fact,  nothing  in  the 
theory  is  more  simple,  if  it  is  true  that 
exophthalmic  goiter  depends  on  hyperfunc- 
tion  of  the  thyroid,  which  hyperactivity  is 
followed  by  an  increased  secretion  of  ad- 
renalin, one  of  the  effects  of  which  will  be 

15  The  same  would  not  be  true  after  thyroparathyroi- 
dectomy.  Eppinger,  Falta  and  Kudinger  admit  in  fact 
that  there  is  an  antagonism  between  the  thyroid  and  the 
parathyroids  and  that  their  actions  on  the  sympathetic 
nervous  system  are  the  reverse  of  one  another,  the 
thyroid  secretion  exciting  and  the  other  inhibiting  the 
nerves  of  this  system.  The  proofs  brought  to  the  sup- 
port of  this  conception  are  insufficient  and  it  is  far  from 
being  established.  Moreover,  F.  Kraus  and  E.  Hirsch 
have  noted  (1909)  that  thyroparathyroidectomized  dogs 
and  rabbits  become  exquisitely  glycosurie  under  the  influ- 
ence of  adrenalin. 

16  According  to  F.  Kraus  and  Eahel  Hirsch,  on  the  con- 
trary, adrenalin  does  not  produce  glycosuria  in  the  dog 
if  thyroid  extract  is  administered  at  the  same  time. 


FUNCTION  OF  THE  GLANDS    203 

glycosuria.  Now,  contrary  to  the  experi- 
ences of  the  Viennese  pathologists,  the  ex- 
periments of  Underhill  and  Hilditch,17  and 
of  Underhill 1S  have  shown  that  glycosuria 
is  exquisitely  produced  after  thyroidec- 
tomy under  the  influence  of  adrenalin. 
Moreover,  E.  P.  Pick  and  F.  Pineles 19 
(1908)  observed  that  the  same  is  true 
in  the  rabbit;  in  the  young  she-goat,  on 
the  contrary,  glycosuria  was  prevented  by 
the  operation.  It  is,  in  fact,  possible  that 
among  thyroidectomized  animals  there  are 
some  that  are  incapable  of  reacting  to  ad- 
renalin. We  know  how  much  the  metabo- 
lism is  disordered  in  these  animals  and  the 

"Frank  P.  Underhill  and  W.  W.  Hilditch,  "Cer- 
tain Aspects  of  Carbohydrate  Metabolism  in  Eelation  to 
the  Complete  Eemoval  of  the  Thyroids  and  Partial  Para- 
thyroidectomy" (Amer.  Jour,  of  Physiol.,  1909,  XXV, 
p.  67). 

18  Frank  P.  Underhill,  ' '  The  Production  of  Gly- 
cosuria by  Adrenalin  in  Thyroidectomized  Dogs"  (Ibid., 
1911,  XXVII,  pp.  331-339). 

19  E.  P.  Pick  and  F.  Pinecles,  "  Tiber  die  Beziehungen 
der  Schilddriise  zur  physiol.  Wirkung  des  Adrenalins" 
(Biochem.  Zeit,  1908,  XII,  p.  473). 


204   THE  INTERNAL  SECRETIONS 

disorders  are  variable  in  intensity ;  if  they 
are  profound  it  is  not  astonishing  that  the 
animal  thus  attacked  cannot  become  hyper- 
glycemic or  glycosuric,  which  has  already 
been  mentioned  above.  This  interpretation 
finds  support  in  a  series  of  experiments 
made  by  H.  Ritzman 20  (1909)  which  show 
that,  in  athyroid  cats,  when  the  phenomena 
of  intoxication  are  acute,  adrenalin  does 
not  provoke  glycosuria;  if  the  disorder  is 
ameliorated  it  reappears.  The  cause  of 
the  absence  of  glycosuria  does  not,  there- 
fore, lie  in  the  lack  of  thyroid  secretion, 
but  in  a  change  of  the  general  condition.21 
Let  us  suppose  the  case  to  be  the  reverse 
of  that  just  examined.  Hyperthyroidism 
brings  after  it  a  stimulation  of  the  chro- 
maffin system  followed  by  emaciation  and 

20 ' '  iiher   den  Mechanismus  der  Adrenalinglycosurie ' 
(Arch.  f.  Exper.  Path,  und  Pharmalc.,  1909,  LXI,  p.  231) 

21  It  is  interesting  to  state  in  this  connection  that  A 
Bonanni  (Arch,  italiennes  de  biologie,  1912,  LVIII,  pp 
157-172)  has  noted  that  the  glycosuria  which  is  pro 
voked  by  carbon  dioxid  is  not  produced  in  debilitated 
animals. 


FUNCTION  OF  THE  GLANDS    205 

glycosuria,  which  are  so  frequently  found 
in  these  conditions  of  thyroid  hyperfunc- 
tion.  But  is  the  reality  of  these  conditions 
firmly  established?  It  is  a  point  that  we 
will  investigate  immediately. 

I  would  like  to  go  immediately  to  the  pith 
of  the  question.  We  might,  to  judge  by 
the  reciprocal  connections  between  the 
chromaffin  system  and  the  thyroid,  insti- 
tute direct  experiments.  It  is  not  always 
possible  to  carry  out  such  experiments; 
the  investigator  is  often  obliged  to  attack 
the  problem  by  indirect  methods  and  he 
can  only  arrive  at  the  solution  sought  for 
by  successive  and  gradual  approximations. 
In  the  case  in  question,  on  the  contrary, 
the  direct  study  is  easy;  the  experiments 
of  Cybulski,  J.  P.  Langlois,  J.  P.  Langlois 
and  L.  Camus,  Biedl,  Dreyer  and  above  all, 
those  of  Tscheboksaroff 22  have  taught  us 

MN.  Cybulski,  "  Tiber  die  Funktion  der  Nebenniere" 
(Wiener  med.  Woch.,  1896,  pp.  215  and  255);  J.  P. 
Langlois,  "Sur  les  fonctions  des  capsules  surrenales, ' ' 
These  de  doctorat  es  sciences,  Paris,  1897;  L.  Camus 


206   THE  INTERNAL  SECRETIONS 

that  the  suprarenal  blood  can  be  collected 
in  quantities  large  enough  to  discover  in 
it  the  action  of  adrenalin  through  the  proc- 
ess of  injecting  this  blood  into  another 
animal.  With  a  view  to  studying  this  ques- 
tion, we  can  call  to  mind  many  other  ex- 
periments. But  there  are  two  series  which, 
it  appears,  should  be  mentioned  first:  (a) 
Is  the  thyroid  secretion  really  an  excitant 
of  the  suprarenal?  And  does  the  supra- 
renal blood  therefore  contain  more  adrena- 
lin after  the  injection  of  thyroid  extract? 
(b)  Do  extracts  of  suprarenal  glands  of 
thyroidectomized  animals  which  have  suc- 
cumbed to  the  operation  contain  less  ad- 
renalin?   On  these  two  points  I  have  col- 

and  J.  P.  Langlois,  "Secretion  surrenale  et  pression 
sanguine"  (C.  B.  de  la  Soc.  de  biol.,  March  3,  1900,  p. 
210)  ;  A.  Biedl,  "Beitrage  zur  physiol.  der  Nebennieren. 
Die  Innervation  der  Nebennieren"  (Arch,  fur  die  ges. 
Physiol.,  1897,  LXVII,  p.  443) ;  George  P.  Dreyer,  "On 
Secretory  Nerves  to  the  Suprarenal  Capsule"  (Am.  Jour, 
of  Physiol.,  1899,  II,  pp.  203-219) ;  M.  Tscheboksaroff, 
"tiber  sekretorische  Nerven  der  Nebennieren"  (Arch. 
fur  die  ges.  Physiol.,  1910,  CXXXVII,  pp.  59-122). 


FUNCTION  OF  THE  GLANDS    207 

lected  a  large  number  of  facts.23  These 
facts  prove  that  the  adrenals  of  thyroidec- 
tomized  animals  do  not  contain  less  active 
adrenalin  than  those  of  normal  animals 
and,  furthermore,  that  the  suprarenal 
blood  does  not  become  richer  in  adrenalin 
after  the  injection  of  thyroid  extract  in 
physiological  doses  than  after  that  of  any 
other  organic  extract,  at  least  of  those 
which  have  been  tested  in  the  experiments 
of  Gley  and  Quinquaud,  viz.,  hepatic,  pan- 
creatic, testicular  and  renal. 

Hence  the  experiments  so  far  carried 
out  do  not  appear  to  favor  either  the  the- 
ory of  the  reenforcing  reciprocal  action  of 
the  thyroid  and  the  adrenals,  or  the  theory 

23 See  E.  Gley  and  Alf.  Quinquaud,  "Contribution 
a  1 'etude  des  interrelations  humorales,  I. — Action  de 
l'extrait  thyroidien  et  en  general  des  extraits  d 'organs 
sur  la  secretion  surrenales"  {Archives  Internationales  de 
physiologie,  January  31,  1914,  XIV,  pp.  152-174)  ;  "Con- 
tribution a  1 'etude  des  interrelations  humorales.  II. — 
Valeur  physiologique  de  la  glande  surrenale  des  animaux 
ethyroideV'  (Ibid.,  pp.  175-194).  See  also  E.  Gley 
and  Alf.  Quinquaud,  C.  B.,  June  30,  1913,  CLVI,  p. 
2013. 


208    THE  INTERNAL  SECRETIONS 

of  the  inhibitory  reciprocal  action  of  the 
pancreas  and  the  adrenals.  Would  it  not 
be  the  same  with  the  other  interrelations 
that  have  been  so  easily  admitted! 

Reciprocal  Relations  between  the 
Thykoid  and  the  Pancreas. — The  third 
case  is  the  interrelation  between  the  thy- 
roid and  the  pancreas.  According  to 
Lorand,24  extirpation  of  the  thyroid  sup- 
presses glycosuria  in  depancreatized  ani- 
mals. Why,  by  what  mechanism1?  The 
answer  given  is  that  following  the  loss  of 
the  inhibitory  influence  exercised  by  the 
pancreas  on  the  thyroid  gland,  the  thyroid 
secretion  is  increased  in  these  depancrea- 
tized animals,  which  is  followed  by  a  sec- 
ondary augmentation  in  the  quantity  of 
adrenalin.25     Hence  if  the  thyroid  is  re- 

21  A.  Lorand,  "Lea  rapports  du  pancreas  (Hots  de 
Langerhans)  avec  la  thyroide"  (C.  B.  de  la  Soc.  de  biol., 
March  19,  1904,  LVI,  p.  488). 

28  We  have  already  seen  that  it  does  not  matter  if 
the  injection  of  thyroid  extract  in  physiological  doses 
does  not  augment  at  all  the  adrenalin  content  of  the 


FUNCTION  OF  THE  GLANDS    209 

moved,  the  secretion  of  adrenalin  dimin- 
ishes and  at  the  same  time  the  hyper- 
glycemia and  the  glycosuria  disappear. 

This  explanation  does  not  take  into  ac- 
count several  important  facts.  The  first  is 
that  in  thyroidectomized  animals  glyco- 
suria has  several  times  been  found;  the 
above  theory  does  not  explain  this — in  any 
case  it  is  seen  that  the  question  is  com- 
plex. Similarly,  cases  of  myxedema  with 
diabetes  have  been  found.  Besides,  let  us 
suppose  that  the  facts  are  always  so.  It 
is  to  be  recalled  that  thyroidectomized  ani- 
mals suffer  from  disordered  metabolic  ex- 
changes, which  are  profoundly  diminished, 
and  that  consequently  glycosuria,26  no  mat- 
ter by  what  cause  it  is  provoked,  may  very 
well  be  diminished  for  this  reason  alone. 
This  is  the  observation  which  has  already 

suprarenal  blood.  The  reasoning  is  therefore  funda- 
mentally wrong. 

"No  one  has  even  attempted  to  investigate  how  the 
various  sorts  of  glycosuria  run  their  course  following 
thyroidectomy. 


210    THE  INTERNAL  SECRETIONS 

been  made  with  regard  to  the  connection 
between  the  pancreas  and  the  adrenals. 
Another  argument  has  also  been  invoked, 
viz.,  the  increase  in  volume  of  the  thyroid 
in  depancreatized  dogs,  combined  with  aug- 
mentation of  the  colloid  substance.27  Taken 
by  itself,  this  statement  does  not  mean 
very  much.  Licini,  more  prudent  than 
others,  has  asked  himself  whether  this  is  a 
compensatory  phenomenon  or  is  it  due  to 
the  suppression  of  a  specific  secretory 
product  of  the  pancreas;  or  perhaps,  we 
may  add,  is  it  a  more  general  phenomenon 
resulting  from  reactions  against  the  intoxi- 
cations which  may  result  from  disorders 
in  the  nitrogenous  metabolism  which  are 
presented  by  depancreatized  dogs. 

Reciprocal  Relations  between  the 
Thyroid  and  the  Gonads. — The  same  un- 
certainty exists  in  connection  with  the  rela- 

27  C.  Licini  (a  pupil  of  Kocher),  "Der  Einfluss  der 
Extirpation  des  Pankreas  auf  die  Schilddriise ' ' 
(Zeitschr.  fur  Chirurgie,  1909,  CI,  p.  522). 


FUNCTION  OF  THE  GLANDS    211 

tions  between  the  thyroid  and  the  ovaries. 
The  ovaries  exercise  an  inhibitory  action 
on  the  thyroid;  in  fact,  the  latter  becomes 
hyperactive  after  castration,  and  there  is 
an  increase  of  colloid  matter.  This  is  the 
cause,  it  is  said,  of  the  large  number  of 
cases  of  exophthalmic  goiter  after  the 
menopause.  Is  it  necessary  to  point  out 
how  very  injudiciously  statistical  methods 
are  applied  here?  The  loss  of  the  thyroid 
function  should  be  followed,  reciprocally, 
by  hyperfunction  of  the  ovary.  The  latter 
has  not  been  proven  at  all.  It  is  true  that 
Champy  and  myself  noted  that  thyroidec- 
tomy in  the  rabbit  is  followed  by  hyper- 
trophy of  the  insterstitial  gland  of  the 
ovary.  But  von  Eiselsberg 2S  showed  long 
ago  that  thyroidectomy  causes  atrophy  of 
the  genital  organs.    The  truth  is  that  these 

28  Fe.  von  Eiselsbeeg,  "  tiber  vegatative  Storungen  im 
Wachstume  von  Thieren  nach  frtihzeitiger  Schilddrusen- 
exstirpation "  (Arch,  fur  Min.  Chirurgie,  1895,  XLIX, 
pp.  207-234).  Cf.  also  a  preliminary  note  in  Berliner 
Min.  Woch.,  1892,  No.  46,  p.  1178. 


212    THE  INTERNAL  SECRETIONS 

statements  of  a  morphological  nature  do 
not  permit  of  drawing  any  conclusions  as 
to  the  direct  connections  between  the  or- 
gans involved. 

Other  interrelations  are  no  better  es- 
tablished. It  is  commonly  thought  that 
when  an  increase  in  volume  is  observed, 
one  may  conclude  a  concomitant  augmen- 
tation of  function.  But  it  is  necessary  to 
prove  first  that  a  hypertrophy  really  cor- 
responds to  functional  hyperactivity.  It 
is  high  time  that  a  physiological  study  be 
made  of  the  organs  thus  stated  to  be  al- 
tered, as  well  as  of  the  properties  of  the 
blood  in  diseases  attributed  to  disorders 
of  internal  secretion.  Without  this  physi- 
ological study  hypotheses  are  being  too 
liberally  formulated. 

That  there  are  connections  between  the 
various  glands  is  one  of  the  fundamental 
facts  maintained  by  the  doctrine  of  inter- 
nal secretions,  and  to  deny  them  would  be 
to  deny  a  part  of  the  doctrine  of  internal 


FUNCTION  OF  THE  GLANDS    213 

secretions  itself.  But  what  I  criticize  is 
the  insufficiently  demonstrated  theory  of 
reciprocal  relations. 

H.      THE   DISEASED   FUNCTION 

From  the  physiological  point  of  view,  the 
diseases  of  the  endocrine  organs  may  be 
divided  into  two  large  classes, — those  at- 
tributed to  hyperfunction,  and  those  to  hy- 
pofunction.  Moreover,  this  is  the  distinc- 
tion most  naturally  made  by  pathologists. 
The  notion  of  insufficiency  has  been  real- 
ized by  physicians,  one  might  say,  from 
time  immemorial.  But  it  has  now  been  de- 
veloped to  such  a  point  that  pathologists 
like  Chaufrard  have  been  led  to  think  that 
this  notion  dominates  pathology.  The  no- 
tion of  excessive  functioning  is  more  recent 
and  has  not  as  large  a  range  as  before  the 
discoveries  relative  to  the  internal  secre- 
tions and  their  disorders. 

Some  reflections  of  a  physiological  na- 


214    THE  INTEBNAL  SECBETIONS 

ture  on  the  value  of  these  two  notions  may 
not  be  out  of  place  here.  As  for  the  clini- 
cal questions  which  confront  us  at  this 
point  in  large  number,  I  have  neither  the 
means  nor  the  intention  to  examine  them. 

( 1 )  Hypersecretion. — I  have  mentioned 
above  that  the  substances  having  a  trophic 
role,  and  hormones,  act  in  minimal  doses. 
It  is  therefore  sufficient  for  the  glands  to 
discharge  very  small  quantities  of  them 
into  the  blood.  This  is  one  of  the  reasons 
why  it  is  so  difficult  to  discover  their  pres- 
ence in  the  blood  of  efferent  veins  of  the 
glands,  at  least  when  we  are  not  dealing 
with  extremely  active  products,  like  secre- 
tin and,  above  all,  adrenalin.  Furthermore, 
these  substances  disappear  very  rapidly 
in  the  blood. 

For  this  reason,  is  it  possible  for  an  ex- 
cess to  remain  in  the  blood?  A  gland  may 
indeed  show  exaggerated  function.  In  or- 
der that  a  morbid  syndrome  be  established 


FUNCTION  OF  THE  GLANDS     215 

in  connection  with  this  hyperfunction,  still 
another  condition  is  necessary;  namely, 
that  the  product  liberated  in  excess  should 
not  be  liable  to  destruction  in  the  blood 
or  tissues.  In  the  conditions  described  as 
resulting  from  glandular  hyperactivity,  no 
one  has  ever  investigated  if  this  second 
condition,  necessary  though  it  is,  is  ful- 
filled. In  view  of  properties  continuously 
manifested,  it  is  most  assuredly  true  that 
there  are  hormones  which  are  constantly 
being  produced.  The  best  example  appears 
to  be  that  of  adrenalin.  But  these  hor- 
mones are  formed  and  secreted  only  in 
very  small  amounts.  In  order  to  admit 
that  a  permanent  state  of  hypersecretion 
exists,  it  would  first  be  necessary  to  dem- 
onstrate that  these  destructive  mechanisms 
have  ceased  to  act.  Just  as  the  excess  of 
digestive  ferments  is  absorbed  or  elimi- 
nated, so  the  endocrine  products  disappear 
rapidly  in  the  blood — secretin  in  several 


216    THE  INTERNAL  SECRETIONS 

minutes,  adrenalin  almost  immediately 
after  it  has  been  injected.29 

Besides,  have  the  states  of  hypersecre- 
tion just  described  indeed  been  proven  to 
exist? 

Hyperthyroidism,  of  which  so  much  has 
been  spoken,  has  never  really  been  repro- 
duced experimentally,  neither  by  Cunning- 
ham, nor  by  Gley,  nor,  in  the  last  few  years, 
in  the  researches  methodically  pursued  by 
Carlson  and  by  Coronedi.30 

No  one  has,  by  repeated  injections  of 
pituitary  extract,  caused  symptoms  of 
acromegaly  to  appear,  no  more  than  symp- 

"  Experiments  of  J.  de  Vos  and  M.  Kochmann  on  the 
rabbit.  One-third  and  even  two-thirds  of  the  minimal 
fatal  dose  of  adrenalin  disappeared  almost  immediately 
after  the  injection  (Arch,  intern,  de  pharmacodyna/nvie, 
1905,  XIV,  pp.  81-91). 

*°B.  H.  Cunningham,  "Experimental  Thyroidism" 
{Jour,  of  Exper.  Med.,  1898,  III,  pp.  147-243);  A.  J. 
Caelson,  J.  E.  Rooks,  and  J.  F.  MacKie,  "Attempts 
to  Produce  Experimental  Hyperthyroidism  in  Mammals 
and  Birds"  (Am.  Jour,  of  Physiol.,  1912,  XXX,  pp.  129- 
159) ;  G-.  Coronedi,  "TJn  coup  d'ceil  d 'ensemble  sur  mes 
experiences  actuelles  relatives  a  la  glande  thyroide" 
(Arch,  italiennes  de  Biologie,  1912,  LVTI,  pp.  252-262). 


FUNCTION  OF  THE  GLANDS    217 

toms  of  exophthalmic  goiter  have  been  pro- 
voked by  injections  of  thyroid  extract.  It 
will  be  remarked  that  the  experiments  of 
Bircher  on  the  reproduction  of  Graves '  dis- 
ease by  intraperitoneal  implantation  of  hy- 
pertrophied  thymus  are  of  an  entirely  dif- 
ferent nature.31 

Does  hypersecretion  of  epinephrin  itself, 
of  which  so  much  has  been  spoken  during 
the  last  few  years,  surely  exist?  Its  real- 
ity in  exophthalmic  goiter  is  well  contest- 
able. While  Meltzer's  reaction  has  been 
obtained  in  the  blood  of  many  patients  suf- 
fering from  exophthalmic  goiter,  yet  the 
serum  of  the  blood  has  not  the  cardiovas- 
cular properties  of  adrenalin  (M.  Cleret 
and  E.  Gley,32  1911) ;  on  the  contrary  its 

31 E.  Bircher,  ' '  Zur  experimentellen  Erzeugung  des 
Morbus  Basedoweii ' '  (ZentraTbl.  fur  Chirurgie,  Feb.  3, 
1912,  XXXIX,  pp.  138-140). 

82  E.  Gley  and  M.  Cleret,  ' '  Kecherches  sur  la  patho- 
genie  du  goitre  exophtalmique.  I.  Action  cardiovascu- 
laire  du  serum  sanguin  des  malades  atteints  de  goitre 
exophtalmique"  {Jour,  de  physiol.  et  de  pathol.  gen- 
erate, 1911,  XIII,  pp.  928-944).    Cf.  also  M.  Cleret  's 


218    THE  INTERNAL  SECRETIONS 

action  is  clearly  hypotensory.  The  hyper- 
tension observed  in  many  renal  affections 
has  also  been  considered  as  a  sign  of  ad- 
renalinemia.  But  Meltzer-Ehrmann's  re- 
action is  not  given  by  the  serum  of  these 
sufferers  and,  furthermore,  Janeway  has 
been  unable  to  discover  any  vaso-constric- 
tive  substance  in  the  blood  of  six  patients 
with  hypertension.  In  this  investigation, 
neither  defibrinated  blood  nor  serum 
should  be  used,  for  these  are  liquids  in 
which  substances  having  a  vaso-constric- 
tive  action  are  formed.33  Also  the  facts 
governing  the  alleged  increase  of  adrena- 
lin in  various  pathological  conditions  can 
no    longer   be    accepted   without   reserve. 

thesis  ("Etude  sur  la  pathogenie  du  goitre  exophtal- 
mique, "  Paris,  1911),  in  which  can  be  found  the  criti- 
cism of  what  I  have  called  the  thyroido-suprarenal  theory 
of  exophthalmic  goiter. 

33 J.  M.  O'Connor,  "tJber  den  Adrenalingehalt  des 
Blutes"  (Arch.  f.  exper.  Pathol,  unci  Pharmak.,  1912, 
LXVII,  pp.  195-232).— Th.  Janeway  and  E.  A.  Park, 
"The  Question  of  Epinephrin  in  the  Circulation  and  its 
Relation  to  Blood  Pressure"  (Jour,  of  Exper.  Med., 
1912,  XVI,  p.  541). 


FUNCTION  OF  THE  GLANDS    219 

Moreover,  in  Lucien  and  Parisot's34  re- 
cent work  will  be  found  the  reasons  why 
we  have  no  right  to  surmise  a  relation  of 
cause  and  effect  from  the  simple  anatomo- 
pathological  fact  of  suprarenal  hypertro- 
phy, and  the  clinical  phenomenon  of  ar- 
terial hypertension. 

(2)  Hyposecretion. — There  are  also 
reasons  for  asking  if  it  is  possible  that  a 
state  of  hypofunction  of  the  endocrine 
glands  is  ever  produced.  This  question  is 
connected  with  that  of  profuse  or  excessive 
functioning,  so  widespread  throughout  the 
organism.  Just  as  machines,  says  Meltzer, 
are  constructed  in  such  a  manner  as  to  pos- 
sess a  resisting  force  superior  to  that  re- 
quired of  them,  so  must  the  animal 35  or- 
ganism have  on  hand  a  superabundance 
of  tissues  and  energy.     There  is  an  ex- 

34  M.  Ltjcien  and  J.  Pakisot,  ' '  Glandes  surrenales  et 
organes  ehromaffines "  (Paris,  ¥.  Gittler,  1913). 

"Meltzer  (loc.  cit.)  wrote  human.  Is  it  not  preferable 
to  say  animal^  The  reader  will  permit  me  to  take  this 
liberty. 


220    THE  INTERNAL  SECRETIONS 

cess  of  digestive  secretions,  excessive  ac- 
tion of  the  heart  and  respiratory  move- 
ments. Similarly,  we  have  surplus  endo- 
crine secretions.  Let  us  recall  the  fact  that 
minimal  doses  of  products  secreted  by  the 
ductless  glands  suffice  to  fulfil  the  role  as- 
signed them. 

Facts  pertaining  to  this  point  are  avail- 
able in  abundance.  A  small  fragment  of 
the  pancreas,  adrenals  or  thyroid,  insignifi- 
cant in  weight  when  compared  to  the  total 
mass  of  the  organ — it  has  been  estimated 
that  a  twelfth  of  the  pancreas  is  sufficient 
to  prevent  glycosuria — preserves  animals 
from  the  fatal  consequences  of  the  extirpa- 
tion of  these  glands.  Undoubtedly,  in  the 
case  of  the  pancreas  it  has  several  times 
been  observed  by  Hedon,  Sandmeyer,  Thir- 
oloix  and  others,  that  animals  in  whom  a 
small  fragment  of  the  gland  has  been 
left,  either  intentionally  or  inadvertently, 
finally  became  diabetic.  One  is  tempted  to 
believe  that  the  fragment  became  insuffi- 


FUNCTION  OF  THE  GLANDS    221 

cient.  Is  it  not  surprising  that  a  portion 
of  an  organ  that,  although  very  small,  has 
sufficed  for  a  long  time  to  maintain  the 
function  of  the  organ,  should  suddenly  lose 
its  ability  to  fulfil  its  office,  although  one 
would  think  that  the  increased  demand  call- 
ing for  hypertrophy  would  increase  its 
functional  capacity?  Sooner  than  accept 
this  hypothesis,  could  we  not  suppose  the 
intervention  of  purely  mechanical  causes 
— adhesions  and  sclerosis,  for  example — 
gradually  rendering  the  circulation  in  the 
remaining  fragment  of  the  organ  difficult, 
which,  furthermore,  has  perhaps  preserved 
but  a  few  small  blood  vessels. 

Another  pertinent  fact  in  this  connection 
is  the  following:  The  suprarenal  glands 
are  more  or  less  severely  attacked  by  vari- 
ous microbic  toxins,  and  the  extract  of 
glands  coming  from  infected  animals  ap- 
pears much  less  active  than  that  from  nor- 
mal glands.  However,  the  arterial  pres- 
sure of  these  animals  is  not  always  very 


222    THE  INTERNAL  SECRETIONS 

low.  This  was  recognized  in  the  case  of 
rabies  in  my  laboratory  by  R.  Porak.36 
Thus  the  small  quantity  of  adrenalin  still 
secreted  by  these  altered  glands  almost 
suffices  to  maintain  the  vascular  tone.  It  is 
more  difficult  than  is  generally  appreciated 
to  render  the  liver  insufficient;  the  blood 
continues  to  contain  sugar  and  urea.  At 
autopsies,  cirrhotic  livers  have  been  found 
in  subjects  in  whom  the  organ  had  ap- 
peared to  function  normally.37 

While  we  thoroughly  understand  insuf- 
ficiencies of  organs  furnishing  mechanical 
labor,  as  the  heart,  or  organs  having  quan- 
titative chemical  functions,  as  the  liver  and 

38  E.  Porak,  ' '  Des  alterations  f  onctionelles  des  glandes 
surrenales  dans  la  rage"  (C.  E.  de  la  Soc.  de  biol.,  Dec. 
7,  1912,  LXXIII,  p.  601). 

37  Almost  the  same  is  true  in  the  case  of  the  kidney. 
Greatly  altered  kidneys  are  found  in  very  many  cadavers, 
although  the  urine  of  the  subjects  had  always  been 
normal  and  they  had  never  presented  any  serious  sign  of 
renal  insufficiency.  It  is  likewise  with  the  blood  which 
certain  pathologists  (Widal  and  his  pupils,  for  example) 
are  investigating  for  signs  of  renal  or  hepatic  insuffi- 
ciency. 


FUNCTION  OF  THE  GLANDS    223 

the   kidneys,    it   is    difficult,    for    reasons 
which  have  just  been  indicated,  to  under- 
stand insufficiencies  of  endocrine  glands, 
since  the  latter  furnish  but  minute  quan- 
tities of  extraordinarily  active  substances 
and  we  must  suppose  them  almost  entirely 
destroyed  in  order  that  they  should  not 
have  the  ability  to  furnish  the  small  quan- 
tity of  secretion  absolutely  necessary  for 
the  vital  functions.     This  does  not  mean, 
however,  that  we  must  deny  a  priori  the 
reality  of  these  insufficiencies,  but  that  we 
should  be  more  stringent  than  heretofore 
in  accepting  demonstrations  of  this  reality. 
Explanation  has  been  much  abused  in  at- 
tempting to  account  for  disorders  of  hypo- 
secretion  and  also,  generally  speaking,  for 
the  disorders  of  all  the  internal  secretions. 
This  has  reached  such  a  point  that  when  a 
syndrome  cannot  be  explained  by  assuming 
either  hypersecretion  or  hyposecretion  of 
an  endocrine  gland,  the  two  factors  are 
brought    in.     Has    it   not   been    said — in 


224    THE  INTEENAL  SECRETIONS 

acromegaly,  for  example — that  there  is  at 
the  same  time  partial  "hyperpituitarism" 
and  "hypopituitarism"?  Would  it  not  be 
right  to  apply  to  this  sort  of  considerations 
and  to  these  pathological  explanations  of 
glandular  disorders  what  Vulpian  wrote 
concerning  pathological  explanations  by 
vaso-motor  disturbances,  at  a  time  when  it 
seemed  to  physicians  that  the  discoveries 
of  physiologists  about  the  action  of  the 
vascular  nerves  could  explain  all  morbid 
phenomena?  "It  was  soon  admitted  that 
the  greater  part  of  the  morbid  disorders 
of  the  organism  had  for  their  origin  or 
mechanism  a  functional  modification  of  the 
vaso-motor  nerves.  Fever,  inflammation, 
hemorrhages,  dyspepsias,  the  chief  neu- 
roses, .  .  .  tetanus,  various  forms  of 
paralysis,  diabetes,  albuminuria,  etc.,  all 
these  pathological  states,  or  at  least  their 
principal  symptoms,  were  due  to  a  pertur- 
bation of  the  vaso-motor  apparatus.  .  .  . 
"For  my  part,  I  have  always  fought 


FUNCTION  OF  THE  GLANDS    225 

against  this  deplorable  tendency  to  apply 
prematurely  facts  from  experimental  phys- 
iology, as  yet  uncertain,  to  pathology.  The 
greater  part  of  the  assertions  thus  made, 
without  any  critical  spirit,  are,  besides, 
absolutely  lacking  in  proof.  They  are 
purely  theoretical  conceptions,  the  results 
of  the  sort  of  speculations  that  can  be 
made  as  one  desires. ' ' 38 

(3)  Trophic  Deviations.  —  It  appears 
certain,  however,  that  there  are  certain  dis- 
eases depending  on  alterations  of  the  en- 
docrine glands.  I  have  posed  the  question, 
Can  toxic  products  not  be  formed  in  the 
endocrine  glands,  the  more  or  less  active 
absorption  of  which  causes  morbid  syn- 
dromes? This  question  confronts  at  once 
experimental  pathology,  pathological  chem- 
istry and  the  clinician.  The  notion  is  un- 
doubtedly hypothetical,  but  there  are  some 
facts  which  render  it  interesting. 

""Vulpian,  "Legons  sur  l'appareil  vaso-moteur, ' '  vol. 
i,  preface,  x,  Paria,  Germer  Bailliere,  1875. 


226    THE  INTERNAL  SECRETIONS 

Among  the  theories  proposed  to  explain 
exophthalmic  goiter,  there  is  one,  dysthy- 
roidism,  which  furnishes  an  example  of  tro- 
phic deviations  with  concomitant  func- 
tional disorders.  I  do  not  mean  by  this 
that  the  theory  of  dysthyroidism  should 
from  now  on  be  considered  as  proved ;  what 
I  do  mean  is  that  if  it  were  definitely  es- 
tablished, it  would  show  the  pathological 
importance  of  functional  deviations.  It  ap- 
pears to  be  demonstrated  that  the  thyroid 
tissue  also  can  be  altered  by  various  influ- 
ences; it  has  been  observed  that  in  many 
infectious  diseases  the  thyroid  secretes  an 
abnormal  colloid  matter  which  does  not 
possess  its  normal  staining  reactions  (M. 
Gamier,  1899) ;  this  is  dysthyroidism.  It 
would  be  interesting  to  investigate  if  this 
altered  tissue  still  manifests  the  physiolog- 
ical properties  of  normal  thyroid  sub- 
stance. Unfortunately,  we  have  as  yet  no 
absolutely  characteristic  test  for  proving 
the  activity  of  the  substance  of  the  thyroid. 


FUNCTION  OF  THE  GLANDS    227 

Speaking  generally,  this  sort  of  studies 
appears  to  me  to  be  very  useful  to  patholo- 
gists. Anatomo-pathological  investigation, 
by  which  the  presence  of  lesions  may  be 
ascertained,  must  be  surpassed.  What 
should  really  interest  the  physician  and  the 
therapeutist  is  a  knowledge  of  the  func- 
tional capacity  of  the  diseased  organ;  the 
lesion  is  of  little  importance  as  long  as  the 
organ  fulfils  its  function.  But,  in  order  to 
make  sure  of  this  last  point,  physiological 
research  is  necessary.  There  are  many  af- 
fections considered  as  glandular  or  pluri- 
glandular in  which  physiological  research 
has  been  completely  neglected  and  which 
are  only  known  through  post  mortem  find- 
ings. And  is  not  the  interpretation  of 
these  findings  uncertain1?  Let  us  take  for 
an  example  the  reaction  of  hyperplasia, 
often  found  in  the  endocrine  glands;  at 
the  time  when  connections  between  these 
glands  were  first  beginning  to  be  perceived, 
this  reaction  was  attributed  to  a  specific 


228    THE  INTERNAL  SECRETIONS 

vicarious  function  (hypertrophy  of  the 
hypophysis  after  thyroidectomy,  for  ex- 
ample). At  present  the  tendency  is  to  con- 
nect it  with  the  suppression  of  a  normally 
antagonistic  action.  Would  it  not  be  pos- 
sible that  the  suppression  of  an  endocrine 
gland  should  be  followed  by  a  special  in- 
toxication, which  would  provoke  in  other 
glands  a  reaction  bordering  on  hyper- 
plasia? In  order  to  judge,  we  must  have 
recourse  to  investigative  procedures  other 
than  the  anatomo-pathological.  Patholo- 
gists are  now  engaged  in  the  field  of  physi- 
ological exploration,  thanks,  above  all,  to 
the  progress  made  in  our  knowledge  of  the 
chemistry  of  the  blood;  but  they  should 
also  make  use  of  the  other  methods  of 
physiology. 

Is  not  the  same  true  of  the  adrenals  I  Is 
it  not  generally  admitted  that  the  effects 
of  extirpation  of  these  organs  do  not  re- 
produce exactly  the  symptoms  of  Addi- 
son's disease?    Are  there  not  cases  of  Ad- 


FUNCTION  OF  THE  GLANDS     229 

dison's  disease  in  which  the  arterial  pres- 
sure is  not  particularly  low?  And  does  not 
the  pigmentation  of  the  skin,  so  character- 
istic in  this  syndrome,  prove  that  the  me- 
tabolism of  the  adrenals  has  undergone  al- 
terations because  of  the  influence  of  the 
morbid  cause  ? 39  And  has  not  Pende  40  re- 
cently attempted  to  explain  the  disorders 
of  acromegaly  by  positing  a  vitiated  pitu- 
itary secretion,  "qualitatively  different 
from  the  physiological  secretion"?  Insuf- 
ficiency or  even  loss  of  function  may  there- 
fore not  constitute  the  entire  disease;  the 
symptoms  may  depend  on  the  disordered 
metabolism  of  the  organ. 

Hence  we  see  that  various  toxic  sub- 
stances— exogenous  as  well  as  endogenous 
poisons — may  act  on  the  glandular  cells. 

59  See  O.  von  Fubth,  "Probleme  der  physiol.  und  der 
pathol.  Chemie,"  Leipzig,  1912,  Bd.  1,  pp.  418-419. 

40 N.  Pende,  "Studio  di  morfologia  e  di  fisiopatologia 
dell  'apparato  ipofisario,  con  speciale  riguardo  alio 
neuroipofisi  ed  alia  patogenesi  dell 'acromegalia"  (II 
Tommasi,  June  10,  1911,  pp.  364-369). 


230    THE  INTERNAL  SECRETIONS 

There  are  some  that  fix  the  cell,  then  it  may 
degenerate  and  atrophy.  Does  not  atro- 
phy of  the  cells  cause  passage  into  the 
blood  of  toxic  substances  that  have  been  re- 
ceived by  them  and  more  or  less  modified, 
and  at  the  same  time  of  cellular  proteins, 
products  of  autolysis  or  degeneration, 
themselves  toxic  f  Let  us  but  recall  what 
occurs  in  cancerous  cachexia,  resulting 
from  the  liberation  of  endocellular  fer- 
ments (F.  Blumenthal).41  These  liberated 
poisons  are  different  according  to  the  or- 
gan in  which  this  process  occurs.  Hence 
the  different  syndromes.  In  some  of  these 
syndromes  it  may  be  that  there  is  nothing 
depending  on  an  actual  insufficiency  of  the 
gland  attacked,  the  parts  which  remain  un- 
affected still  assuring  enough  of  the  spe- 
cific function;  but  the  metabolism  of  the 
gland  itself  is  changed  and  this  is  perhaps 

41 F.  Blumenthal,  "Die  chemischen  Vorgange  bei  der 
Krebskrankheit ' '  (Ergebnisse  der  Physiol.,  1910,  X,  pp. 
363-428). 


FUNCTION  OF  THE  GLANDS     231 

enough  to  cause  trouble.  At  least,  we  may 
indicate  this  opportunity  for  investigation. 
The  problem  is  complex.  Physiology  has 
furnished  the  foundations  and  traces  its 
limits;  the  solution  will  be  the  result  of 
extensive  analysis,  in  which  physiology 
will  play  its  part,  but  which  will  no  less  re- 
sult from  the  convergent  efforts  of  clini- 
cal science,  experimental  pathology  and 
chemistry. 


INDEX 


INDEX 


Absorption,  83 

and  secretion,  84 
Acromegaly,  71 

not  produced  experimen- 
tally, 216 
Addison's  disease,  71 
and  extirpation  of  adre- 
nals, 228 
Adrenalin,  91,  92 
action  of,  161 
and    dilatation    of    the 

pupils,  195 
and  nutritive  exchanges, 

199 
and  sympathetic  nervous 

system,   187 
and  vagotonia,  26 
effect   of    successive    in- 
jections of, 
in     depancreatized     ani- 
mals, 196 
in  venous  blood,  100 
Adrenalinemia,  218 
Adrenals,  action  when  dis- 
eased, 221 
Albumoses     and     secretin, 

179-80 
Anaphylaxis,  119 
Ancel,  102 
Aschner,  102 

Autonomotropic    hormones, 
existence  of,  190 

Basch,  81,  101 
Bayer,  200 


Bayliss,  146 
Beclard,  30,  46 
Bernard,    Claude,    16,    43, 
46,  47,  50,  73 
ideas  of,  on  internal  se- 
cretions, 32  ff. 
influence  of  work  of,  40- 

41 
summary     of     contribu- 
tions of,  40 
Bert,  Paul,  47 
Berthold,  30,  31 
Bibliography,   56,    66-69 
Biedl,  19,  20,  23,  25,  30,  31, 
57,  59,  87,  109,  154 
Bile,    absorption    of,    into 
blood,   23 
and     thyroid     secretion, 
180 
Blazek,  pygopagus  monster, 

102 
Blood,    absorption    of    bile 
into,  23 
of   seminal  fluid  into, 
22 
and   secretions,  relations 

of,  17  et  seq. 
influences  of  diseases  of 
spleen  on,  28 
of  thyroid  on,  28 
modification  of,  by  inter- 
nal secretions,  51  et 
seq. 
relations  of,  to  secretory 
glands,  32 


235 


236 


INDEX 


Blood,     specific    glandular 
products  in,  63,  93, 
94 
venous,  secretion  in,  99 

Blood  glands,  27,  37 

Blood  pressure,  regulation 
of,  by  internal  se- 
cretions, 63-65 

Bones,  growth  of,  137,  138, 
139 

Bordeu,  Theophile,  as  dis- 
coverer   of    internal 
secretions,  19  ff. 
as    pathologist,    23,    25, 
27 

Bouin,  85,  102 

Brown-Sequard,  12,  16,  32, 
42,  50,  56,  65 
founder   of    doctrine   of 

secretions,  55,  59 
fundamental     work     of, 
51-54 

Burdach,  27,  46 

Cachexias,  24 

Calzolari,  81 

Cannon,  182 

Carbon  dioxid,  as  excitant, 
146-147 
as  a  hormone,  104 
classification    and    func- 
tion of,   150-151 

Carlson,   79 

Castration  and  respiratory 
exchanges,  159 

Cellular  excretions,  physio- 
logical rdle  of,  152- 
153 

Cerebro-spinal   fluid,   86-87 

Cesa-Bianchi,   119,    120 

Champy,  85,  115,  120 

Chromaffin  system,  hyper- 
activity of,  200 


Classification  of  endocrine 
glands     and     prod- 
ucts, 167  ff. 
chemical,  168 
tables,  172  ff. 
of  endocrine  products, 
gaps  in,  169 
physiological,  169 
Coronedi,  79 

Corpora     lutea,     vasodila- 
tator    action     of, 
124 
Cozzolino,  81 
Crile,  182 
Cunningham,   79 
Cybulski,  57 
Cyon,  E.  de,  104 

Dale,  161 
Delezenne,  99 
Development,      phenomena 

of,  166-67 
Diabetes,  71 

and    the    adrenals,    197- 

198 
"negative,"  199 
relations    of    lesions    of 
pancreas  to,  70 
Dreyer,  57 

Dysthyroidism,  theory  of, 
226 

Ehrlich,  164 

Endocrine  glands,  connec- 
tions between,  183 
ff. 

diseased  function  of,  213 
ff. 

normal      activities      of, 
177  ff. 

study  of,  12 

with    double    enervation, 
188 


INDEX 


237 


Endocrine  products,  action 
of,  in  minimal  doses, 
220  ff. 
classification  of,   167  ff. 
distinctive      characteris- 
tics of,   156  ff. 
likenesses     and      differ- 
ences of,   168 
tables  of,  172-74 

Enriques,  100 

Epigenesis,    159 

Epinephrin,  hypersecretion 
of,  217 

Eppinger,  Falta  and  Kud- 
inger,  diagram  of, 
184-85,    201 

Eppinger  and  Hess,  189 

Ergastoplasm,  88 

fitienne,  122 

Excretory  products,  as  ex- 
citants, 148 

Findlay,  86 

Fleig,  100 

Floerken,  81 

Foa,  103 

Forschback,  97 

Founders  of  doctrine  of 
internal  secretions, 
32 

v.  Frankl-Hochwart,  123 

Frouin,  197 

Functional  correlations,  156 

Functional  humoral  corre- 
lations, 54 

Funke,  46 

Gachet,  81 

Galactogogue        action, 

glands  having,  117 
Galactogogue  hormone,  102 
Galeotti,  86 
Girard,  86,  87 


Gland,  conception  of,  147, 

148 
Glands,  blood,  27,  37 
secretory,     relations     of 

blood  to,  32 
two  classes  of,  37 
with     double     secretory 
function,    86 
Glandular  discharge,  excit- 
ants of,  179  ff. 
Glandular   products,   speci- 
fic, 94 
Gley,  52,  55,  56,  58,  79,  96, 
98,    106,    115,    120, 
216 
Glover,  57 
Glycose,  91 

Glycosuria,     after     thyroi- 
dectomy, 203 
and  the  adrenals,  197 
extirpation     of     thyroid 

in,  208-10 
in    exophthalmic    goiter, 
202 
Grigoriu,  102 
Gull,  48 
Gray,  46 

Hallion,   100 
Harley,  58 

Harmozones,  134,  142,  156 
Hedon,  58,  97,  98 
Heidenhain,    84 
Henderson,  81 
Henle,  27,  28 
Herring,  123 
Herzen,  80,  96 
Hippocratic  school,  25 
Homostimulants,  181 
Hormonal,  129,   130 

dangers  of,  131 
Hormone,  65,  131,  132,  143 
ff. 


238 


INDEX 


Hormone,     chemical,     143- 
144 
galactogogue,  102 
mammary,  101 
physiological,    143-144 
Hormones,  157 

action    of,    in    minimal 

doses,  214 
characteristics  of,  158 
general  action  of,  167 
local  action  of,  165 
specificity  of,  159 
transitory  action  of,  164 
Howell,  122 
Humoral   interrelations, 

theory  of,  191 
Hypersecretion  of  glandu- 
lar products,  214 
Hyperthyroidism,    216 
Hypertony    of    sympathet- 
ic   nervous    system, 
26 
Hyposecretion  of  endocrine 
products,  219  ff. 
reality   of,    222-225 

Internal  medium,  85 
Internal  secretions,  35  ff. 
chemical  condition  of,  89- 

92 
concept  of,  15,  47  ff. 

present,  57  ff. 
conditions  necessary  for, 

77  ff. 
definition  of,  35 
distinctive  characteristics 

of,  134  ff. 
founders  of  doctrine  of, 

32 
histological  condition  of, 

82-89 
physiological      condition 

of,  82 


Internal     secretions,     pre- 
cursors of    doctrine 
of,  16 
regulating    development, 
137-140 

Internal  secretory  glands, 
characteristics  of,  77 
ff. 

Intestinal  mucous  mem- 
brane, 82,  83 

Iodothyrin,  61 

Iodothyroglobulin,  92 


Kocher,  48 
Kolliker,  27,  29 
Kraus,  187 


Laennec,  13 
Lambert,  109 
Lancereaux,  70 
Lane-Claypon,   103 
Langlois,  57 

Legallois,  ideas  of,  indefi- 
nite, 18 

views  of,  on  glands,  17 
Lepine,  58 
Lewandowsky,   108 
Licini,  210 
Liegeois,  45 
Liver,  37 

as  endocrine  gland,  33 

functions  of,  39 

secretion  of,  32 
Loewi,  195-96 
Longuet,  30,  42 
Lorand,  208 
Lucien,  81 
Lungs,  37 
Lymph,   role   of,   26 
Lymphatic    path,    87 
Lymphatic  veins,  22 


INDEX 


239 


Mammary  hormone,  101 
Meltzer,  72,  148,  151,  152 
Mendel,  96 
Mering,  von,  57,  70 
Milne-Edwards,  30 
Minkowski,   57,  58,  70,  97 
Mironoff,  63,  101 
Morphogenetic    substances, 

104,  134,  157 
necessity    of,    for    term, 

135-136 
Miiller,  26,  27,  30 
Murray,  56 
Myxedema,  56 

Nervous  system,  and  inter- 
nal secretion,  181 
and  thyroid,  182 

Neuberger,  19,  23 

Neurochemical  correlations, 
66 

Nutritive     materials,     91, 
134 

Nutritive     transmutations, 
149 

Obersteiner,  86 
Opotherapy,       associative, 

193 
Oppel,  84 
Ord,  48 

Organic     extracts,     action 
of,  105  ff. 
advantages  from  use  of, 

133 
effects  of  large  doses  of, 

127 
errors  involved  in  use  of, 

108 
factors   involved   in   use 

of,  116 
objections  of  fact  to  use 
of,  115 


Organic  extracts,  pharma- 
codynamic action  of, 
126 
theoretical  objections  to 

use  of,  113 
value  of,  106 
Ostwald,  A.,  92 
Ott,  117 

Pachon,  95,  98 

Pancreas,  58,  95 

action  when  partially  ex- 
tirpated, 220-21 
and  adrenals,  reciprocal 
relations       between, 
195 
and  spleen,  relations  of, 

43,  50 
proof  of  internal  secre- 
tion, 96-98 
relations    of,    with    thy- 
roid,  185 
relations   of    lesions   of, 
to  diabetes,  70 

Parabiosis,  97 

Parathyroids,  antitoxic 
mechanism  of,  171 

Parhormones,  146,  154 

Parisot,  81,  122 

Pathology  and  endocrine 
glands,  70 

Paton,  81 

Patta,  115 

Pettit,  86,  87 

Pfliiger,  84 

Phenylsulphates,  88,  151 

Physiological  differentia- 
tion, evolution  of, 
162-164 

Physiological  investigation 
of  endocrine  glands, 
necessity  for,  227- 
229 


240 


INDEX 


Pick  and  Pineles,  203 

Pituitary,  action  of,  161 
effects  of  extirpation  of, 
137 

Pituitary  extract,  action 
of,  on  bladder,   123 

Pluriglandular  insufficien- 
cy, syndromes  of, 
192 

Poisons,  exogenous  and 
endogenous,  229-30 

Preformation,  theory  of, 
159 

Prenant,  85 

"  Proadrenalin, "  179 

Prostate,  secretion  of,  144 

Reciprocal     glandular    ac- 
tions, 182  ff. 
and    interrelations,    182- 
183 

Refluxes,  25 

Renon,  191-92 

Rettger,  96 

Reverdin,  A.,  48,  71 

Reverdin,  J.  L.,  48,  71 

Ribbert,  101 

Robin,  44,  45,  47 

Roger  and  Josuet,  123 

Schafer,  57,  103,  107,  117, 

123 
Schiff,  43,  48,  50 
Schroder,  von,  104 
Scott,  117 
Secretin,  92 

correlations     established 

by,  165,  166 

in   venous   blood,   99 

sources  of,  161 

Secretion,  internal,  concept 

of,  15  et  seq. 

present,  59  et  seq. 


Secretion,  internal,  found- 
ers of    doctrine   of, 
32 
precursors     of     doctrine 
of,  16 
Secretions,  blood  and,  rela- 
tions of,  17  et  seq. 
externo-internal,  87 
importance   of,   12 
interno-external,  87 
kinds  of,  11 
Secretory  glands,  relations 

of  blood  to,  32 
Secretory    products,    desti- 
nation of,  149 
Seminal    fluid,    absorption 

of,  into  blood,  22 
Semon,  71 
Soli,  81 
Sommer,   81 

Specific     glandular     prod- 
ucts, 63,  94,  178-179 
and  katabolism,  64-65 
detection  of,  in  blood,  93 
Spleen,   80,   95,    96 

and    pancreas,    relations 

of,  43,  50 
diseases    of,    and    influ- 
ence on  blood,  28 
Starling,   65,   69,   103,   146 
Status     lymphaticus,     128, 

130 
Studnicka,  87 
Substitution  therapy,  170 
Suprarenal  extract,  cardio- 
vascular   action    of, 
107 
Suprarenin,  158 
Szmonovicz,  57 
Sympathetic    nervous    sys- 
tem,   hypertony    of, 
26 
Sympathicotonia,  189 


INDEX 


241 


Tachyphylaxia,  119 
crossed,  120 
importance  of,  121 
Temperaments,  24 
Testicles,    extirpation    and 
grafting  of,  30 
extract  of,  55 
lymphatic  veins  in,  22 
Tigerstedt,  145 
Thiroloix,  58,  97 
Thymus,  80 

and  growth  of  bone,  160 
Thyroid   gland,    and    adre- 
nals, reciprocal  rela- 
tions between,  201 
and    gonads,    reciprocal 
relations       between, 
210  ft. 
and  nutrition,  62 
and  pancreas,  reciprocal 
relations       between, 
208  ft. 
as  excitant  of  adrenals, 

206-207 
as      internal      secretory 

gland,  80 
diseases  of,  influences  of, 

on   blood,  28 
function  of,  48,  49 
relations  with   pancreas, 

184-86 
removal  of,  48,  56 
transplantation  of,  49 
Thyroid  secretions,  70 
and  vagus,  187 


Thyroidectomy,  metabolic 
disorders  after,  209 

Trophic  deviations  in  en- 
docrine glands, 
225  ff. 

Trunecek,  102 

Underhill  and  Hilditch,  203 

Urea,   91,   104 

as  excitant,  146,  147 
classification  of,  146 

Uric  acid,  151 

Vagotonia,  26,  189 

disorders    arising    from, 
190-91 

Vascular  glands,  27,  37 

Vassale,  56 

Vegetative  nervous  system 
and  reciprocal  glan- 
dular activities,  187, 
189-90 

Veins,  lymphatic,  22 

Venous  blood,  properties 
of,   105 

Vincent,  88,  122 

Vulpian,  42 

Waste    products    as    excit- 
ants, 103 
Waterman,    125 
Wertheimer,  100 
Wilson,  159 

Ziilzer,  132 


MEDICAL  MONOGRAPHS 

Published  by 

PAUL  B.   HOEBER 

67-69  East  59th  St.,  New  York 

This  catalogue  comprises  only  our  own  publications.  It  will 
be  noticed  that  particular  care  has  been  exercised  in  the  selec- 
tion of  Monographs  of  timely  interest. 

We  are  always  glad  to  consider  the  publication  of  new  and 
original  medical  worlcs.  Correspondence  ivith  Authors  is 
invited.  ,\ 

ADAM:     Asthma  and  Its  Eadical  Treatment.     By  James 
Adam,   M.A.,   m.d.,   f.r.c.p.s.     Hamilton.     Dispensary  Aural 
Surgeon,  Glasgow  Eoyal  Infirmary. 
8vo,  Cloth,  viii+184  Pages,  Illustrated $1.50  net. 

ADLEE:  Primary  Malignant  Growths  of  the  Lungs  and 
Bronchi.  By  I.  Adler,  a.m.,  m.d.,  Professor  Emeritus  at  the 
New  York  Polyclinic,  Consulting  Physician  to  the  German, 
Beth-Israel,  Har  Moriah,  and  People's  Hospitals,  and  Mon- 
tefiore  Home  and  Hospital.  8vo,  Cloth,  xii+325  Pages,  1 
Colored  and  16  Halftone  plates $2.50  net. 

AMEEICAN  JOURNAL  OF  EOENTGENOLOGY,  THE. 
Official  Organ  of  the  American  Eoentgen  Eay  Society. 
Edited  by  James  T.  Case,  m.d.,  Battle  Creek,  Mich.  Pub- 
lished Monthly  (Volume  IV,  No.  1.  Published  January, 
1917).     $5.00  per  year. 

ANNALS  OF  MEDICAL  HISTOEY.  Edited  by  Francis  E. 
Packard,  m.d.  Associate  Editors:  Drs.  Harvey  Cushing, 
George  Dock,  Mortimer  Frank,  Fielding  H.  Garrison,  Abra- 
ham Jacobi,  Howard  A.  Kelly,  Arnold  C.  Klebs,  Sir  William 
Osier,  Lewis  S.  Pilcher,  David  Eiesman  and  Edward  C. 
Streeter.    Published  quarterly,  $6.00  per  year. 

1 


2  EOEBEB'S  MEDICAL  MONOGRAPHS 

ARMSTRONG:  I.  K.  Thebapy,  with  Special  Reference  to 
Tuberculosis.  By  W.  E.  M.  Armstrong,  m.a.,  m.d.  Dublin. 
Bacteriologist  to  the  Central  London  Ophthalmic  Hospital, 
Late  Assistant  in  the  Inoculation  Department,  St.  Mary's 
Hospital,  Padding,  W. 
8vo,  Cloth,  x-j-93  Pages,  Illustrated $1.50  net. 

BACH:  Ultra-Violet  Light  by  Means  op  the  Alpine  Sun 
Lamp.  By  Hugo  Bach,  m.d.,  Bad  Elster,  Saxony,  Germany. 
Authorized  Translation  from  the  German.  114  Pages,  HIub- 
trated    $1.00   net. 

BIGG:  Indigestion,  Constipation  and  Liver  Disorder.  By 
G.  Sherman  Bigg,  Fellow  of  the  Koyal  College  of  Surgeons; 
Fellow  of  the  Royal  Institute  of  Public  Health ;  Late  Surgeon 
Captain,  Army  Medical  Staff;  Surgeon  Allahabad,  India, 
12mo,  Cloth,  viii+168  Pages $1.50  net. 

BEAUN  AND  FRIESNER:  Cerebellar  Abscess:  Its  Eti- 
ology, Pathology,  Diagnosis  and  Treatment.  (See  Friesner 
&  Braun) $2.50  net. 

BBOCKBANK:  The  Diagnosis  and  Treatment  op  Heart 
Disease.  Practical  Points  for  Students  and  Practitioners. 
By  E.  M.  Brockbank,  m.d.  (Vict.),  f.r.c.p.,  Hon.  Physician, 
Royal  Infirmary,  Manchester,  Clinical  Lecturer  on  Diseases 
of  the  Heart,  Dean  of  Clinical  Instruction,  University  of 
Manchester. 
12mo,  Cloth,  2nd  Edition,  120  Pages,  Illustrated.  .$1.50  net. 

BROWNE:  Religio  Medici,  Letters  to  a  Friend,  etc.,  and 
Christian  Morals.  2nd  Edition,  with  Preface  by  Drs.  Osier 
and  Packard In  Preparation. 

BRUCE:     Lectures  on  Tuberculosis  to  Nurses.    Based  on 
a  course  delivered  to   the   Queen  Victoria  Jubilee   Nurses. 
By  Olliver  Bruce,  m.r.c.s.,  l.r.c.p.,  Joint  Tuberculosis  Officer, 
County  of  Essex. 
12mo,  Cloth,  124  Pages,  Illustrated $1.00  net. 

BRUNTON:     Therapeutics    op   the    Circulation.    By   Sir 
Lauder    Brunton,     m.d.,     d.sc,    ll.d.    Edin.,    ll.d.    Aberd., 
f.r.c.p.,   p.r.s.     Consulting  Physician  to  St.   Bartholomew's 
Hospital.     Second  Edition,  Entirely  Revised. 
Cloth,  xxiv+536  Pages,  110  Illustrations $2.50  net. 

BULKLEY:     Cancer:    Its  Cause  and  Treatment,  Volume 
I.     By  L.  Duncan  Bulkley. 
8vo,  Cloth,  224  Pages $1.50  net. 

BULKLEY :  Cancer  :  Its  Cause  and  Treatment,  Volume  n. 
By  L.  Duncan  Bulkley.    8vo,  Cloth,  272  Pages $1.50  net. 


EOEBEB'S  MEDICAL  MON  OGB  APES  3 

BULKLEY:  Compendium  of  Diseases  of  the  Skin.  Based 
on  an  analysis  of  thirty  thousand  consecutive  cases.  With 
a  Therapeutic  Formulary,  by  L.  Duncan  Bulkley,  A.M., 
m.d.  Physician  to  the  New  York  Skin  and  Cancer  Hospital; 
Consulting  Physician  to  the  New  York  Hospital. 
8vo,  Cloth,  xviii+286  Pages $2.00  net. 

BULKLEY:     Diet  and  Hygiene  in  Diseases  of  the  Skin. 
By  L.  Duncan  Bulkley. 
8vo,  Cloth,  xvi-j-194  Pages $2.00  net. 

BULKLEY:  The  Influence  of  the  Menstrual  Function 
on  Certain  Diseases  of  the  Skin.  By  L.  Duncan  Bulkley. 
12mo,  Cloth,  108  Pages $1.00  net. 

BULKLEY:  Principles  and  Application  of  Local  Treat- 
ment in  Diseases  of  the  Skin.  By  L.  Duncan  Bulkley. 
12mo,  Cloth,  130  Pages $1.00  net. 

BULKLEY:     The  Relations  of  Diseases  of  the  Skin  to 
Internal  Disorders  :  With  Observations  on  Diet,  Hygiene 
and  General  Therapeutics.     By  L.  Duncan  Bulkley. 
12mo,  Cloth,  175  Pages $1.50  net. 

CARREL  AND  DEHELLY:  Treatment  of  Infected 
Wounds.  By  A.  Carrel  and  G.  Dehelly.  Authorized  Transla- 
tion from  the  French  by  Col.  Charles  Herbert  Fagge,  m.d., 
f.r.c.s.,  of  Guys  Hospital,  London,  England In  Press. 

CAUTLEY:     The  Diseases  of  Infants  and  Children.     By 
Edmund  Cautley,  m.d.  Cantab.,  f.r.c.p.  Lond.    Senior  Physi- 
cian to   the  Belgrave  Hospital  for  Children;    Physician  to 
the  Metropolitan  Hospital;  etc. 
Large  8vo,  Cloth,  1042  Pages $7.00  net. 

CLARKE :  Problems  in  the  Accommodation  and  Refraction 
of  the  Eye,  a  Brief  Review  of  the  Work  of  Donders, 
and  the  Progress  Made  During  the  Last  Fifty  Years.  By 
Ernest  Clarke,  m.d.,  b.s.,  f.r.c.s.  Senior  Surgeon  to  the 
Central  London  Ophthalmic  Hospital,  Consulting  Ophthalmic 
Surgeon  to  the  Miller  General  Hospital. 
8vo,  Boards,  110  Pages $1.00  net. 

COOKE:  The  Position  of  the  X-Rays  in  the  Diagnosis 
and  Prognosis  of  Pulmonary  Tuberculosis.  By  W.  E. 
Cooke,  m.b.,  m.r.c.p.e.,  d.p.h.  (Lond.),  Medical  Superin- 
tendent, Ochil  Hills  Sanatorium  and  Coppins  Green  Industrial 
Sanatorium.    8vo,  Cloth,  Illustrated $1.50  net. 

COOPER:  Pathological  Inebriety.  Its  Causation  and 
Treatment.  By  J.  W.  Astley  Cooper.  Medical  Superin- 
tendent and  Licensee  of  Ghyllwood  Sanatorium  near  Cocker- 
mouth,  Cumberland.  With  Introduction  by  Sir  David  Fer- 
rier,  m.d.,  f.b.s.    12mo,  Cloth,  xvi+151  Pages $1.50  net. 


4  HOEBER'S  MEDICAL  MONOGRAPHS 

COOPER:    The  Sexual   Disabilities   of  Man,  and   Their 
Treatment.    By  Arthur  Cooper.    Consulting  Surgeon  to  the 
Westminster  General  Dispensary;   Formerly  Surgeon  to  the 
Male  Lock  Hospital,  London. 
3rd  Edition,  12mo,  Cloth,  viii+227  Pages $2.50  net. 

COEBETT-SMITH :  The, Problem  op  the  Nations.  A  Study 
in  the  Causes,  Symptoms  and  Effects  of  Sexual  Disease,  and 
the  Education  of  the  Individual  Therein.  By  A.  Corbett- 
Smith,  Editor  of  The  Journal  of  State  Medicine;  Lec- 
turer in  Public  Health  Law  at  the  Royal  Institute  of  Public 
Health.    Large  8vo,  Cloth,  xii+107  Pages $1.00  net. 

CORNET :     Acute  General  Miliary  Tuberculosis.    By  Pro- 
fessor  Dr.   G.  Cornet,   Berlin  and  Reiehenhall.     Translated 
by  F.  S.  Tinker,  b.a.,  m.b.,  etc. 
8vo,  Cloth,  viii-j-107  Pages $1.50  net. 

CROOKSHANK:     Flatulence  and  Shock.    By  F.  G.  Crook- 
shank,  m.d.  Lond.,  m.r.c.p.    Physician  (Out  Patients)  Hainp- 
stead  General  and  N.  W.  Lond.  Hospital ;  Assistant  Physician 
The  Belgrave  Hospital  for  Children  S.  W. 
8vo,  Cloth,  iv-f-47  Pages $1.00  net. 

DAVIDSON:  Localization  by  X-Rays  and  Stereoscopy. 
By  Sir  James  Mackenzie  Davidson,  m.b.,  cm.  Aberd.  Con- 
sulting Medical  Officer,  Roentgen  Ray  Department,  Royal 
London  Ophthalmic  Hospital,  and  X-Ray  Department,  Char- 
ing Cross  Hospital;  Fellow,  Physical  Society;  President, 
Radiology  Section,  Seventeenth  International  Congress  of 
Medicine.  8vo,  Cloth,  72  Pages,  Plates  and  58  Stereoscopic 
Figures    $3.00  net. 

DELORME:  War  Surgery.  By  Edmond  Delorme,  General 
Medical  Inspector  of  the  French  Army.  Translated  by  D. 
De  Merie,  Surgeon  to  In-Patients,  French  Hospital,  London. 
12mo,  Cloth,  Illustrated,  248  Pages $1.50  net. 

EDRIDGE-GREEN:  The  Hunterian  Lectures  on  Colour- 
Vision  and  Colour  Blindness.  Delivered  before  the  Royal 
College  of  Surgeons  of  England  on  February  1st  and  3rd, 
1911.  By  Professor  F.  W.  Edridge-Green,  m.d.  Durh., 
p.r.c.s.  England.  Beit  Medical  Research  Fellow. 
8vo,  Cloth,  x-f76  Pages $1.50  net. 

EHRLICH:  Experimental  Researches  on  Specific  Thera- 
peutics. By  Prof.  Paul  Ehrlich,  m.d.,  d.sc.  Oxon.  Director 
of  the  Konigliches  Institut  fur  Experimentelle  Therapie, 
Frankfort.  The  Harben  Lectures  for  1907  of  The  Royal 
Institute  of  Public  Health. 
16mo,  Cloth,  x-f95  Pages $1.00  net. 

EINHORN:  Lectures  on  Dietetics.  By  Max  Einhorn, 
Professor  of  Medicine  at  the  New  York  Post-Graduate  Med- 


HOEBEB'S  MEDICAL  MONOGBAPHS  5 

ical   School    and    Hospital    and    Visiting    Physician    to    the 

German  Hospital,  New  York. 

12mo,  Cloth,  xvi+156  Pages $1.25  net. 

ELLIOT:     Glancoma.     By    Col.    Eobert   Henry    Eliot,    m.d., 

F.R.C.S. 

8vo,  Cloth,  about  150  Pages,  Illustrated  with  plates 

and  text  illustrations In  Press. 

ELLIOT :     Scleko- Corneal     Trephining  in   the  Operative 
Treatment  op  Glaucoma.     By  Robert  Henry  Elliot,  m.d., 
b.s.   Lond.,   d.sc.    Edin.,   f.r.c.s.   Eng.,   etc.     Lieut.    Colonel 
i.m.s.     Second   Edition. 
8vo,  Cloth,  135  Pages,  33  Illustrations $3.00  net. 

EMERY :  Immunity  and  Specific  Therapy.  By  Wm.  D  'Este 
Emery,  m.d.,  b.sc.  Lond.  Clinical  Pathologist  to  King's 
College  Hospital  and  Pathologist  to  the  Children's  Hospital, 
Paddington  Green;  formerly  Assistant  Bacteriologist  to  the 
Royal  College  of  Physicians  and  Surgeons,  and  some  time 
Lecturer  on  Pathology  and  Bacteriology  in  the  University 
of  Birmingham. 

8vo,  Cloth,  448  Pages,  with  2  Illustrations $3.50  net. 

adopted  by  the  u.  s.  army. 

FISHBERG:     The  Internal  Secretions.     (See  Gley.) 

FRIESNER  AND  BRAUN:  Cerebellar  Abscess;  Ita  Eti- 
ology, Pathology,  Diagnosis  and  Treatment.  By  Isidore 
Friesner,  m.d.,  f.a.c.s.,  Adjunct  Professor  of  Otology  and 
Assistant  Aural  Surgeon,  Manhattan  Eye,  Ear  and  Throat 
Hospital  and  Post.  Graduate  Medical  School,  and  Alfred 
Braun,  m.d.,  f.a.c.s.,  Assistant  Aural  Surgeon,  Manhattan 
Eye,  Ear  and  Throat  Hospital,  Adjunct  Professor  of 
Laryngology,  New  York  Polyclinic  Hospital  and  Medical 
School  and  Adjunct  Otologist,  Mt.  Sinai  Hospital.  8vo,  Cloth, 
about  200  Pages,  10  Plates,  16  Illustrations $2.50  net. 

GERSTER:  Recollections  of  an  American  Surgeon.  By 
Arpad  G.  Gerster,  m.d In  Press. 

GHON:     The    Primary   Lung   Focus   of   Tuberculosis   in 
Children.     By  Anton   Ghon,  m.d.,   English   Translation  by 
D.  Barty  King,  M.A.,  m.d.  Edin.,  m.r.c.p.,  Assistant  Physician 
to  the  Royal  Hospital  for  Diseases  of  the  Chest. 
196  Pages,  72  Text  Figures  and  2  Plates $3.75  net. 

GILES:  Anatomy  and  Physiology  of  the  Female  Genera- 
tive Organs  and  of  Pregnancy.  By  Arthur  E.  Giles,  M.D., 
b.sc.  Lond.,  m.r.c.p.  Lond.;  f.r.c.s.  Ed.  Gynecologist  to  the 
Prince  of  Wales  General  Hospital,  Tottenham,  and  Surgeon 
to  the  Chelsea  Hospital  for  Women. 
Large  8vo,  24  Pages,  with  Mannikin $1.50  net. 


6  EOEBEB'S  MEDICAL  MONOGBAPES 

GrLEY:    The  Internal  Secretions.    By  E.  Gley,  m.d.    Mem- 
ber  of    the   Academy   of    Medicine   of   Paris,   Professor   of 
Physiology  in  the  College  of  France,  etc.    Authorized  Trans- 
lation, Translated  and  Edited  by  Maurice  Fishberg,  m.d. 
Svo,  Cloth,  241  Pages $2.00  net. 

GOULSTON:  Cane  Sugar  and  Heart  Disease.  By  Arthur 
Goulston,  m.a.,  m.d.  Cantab.  Hunterian  Society's  Medallist, 
1912.    8vo,  Cloth,  107  Pages $2.00  net. 

GEEEFF:  Guide  to  the  Microscopic  Examination  op  thb 
Eye.  By  Professor  E.  Greeff.  Director  of  the  University 
Ophthalmic  Clinique  in  the  Eoyal  Charity  Hospital,  Berlin. 
With  the  co-operation  of  Professor  Stock  and  Professor 
Wintersteiner.  Translated  from  the  third  German  Edition 
by  Hugh  Walker,  m.d.,  m.b.,  cm.  Ophthalmic  Surgeon  to 
the  Victoria  Infirmary,  Glasgow. 
Large  Svo,  Cloth,  86  Pages,  Illustrated $2.00  net. 

HAEEIS:  Lectures  on  Medical  Electricity  to  Nurses, 
An  Illustrated  Manual  by  J.  Delpratt  Harris,  m.d.  Durh., 
m.r.c.s.  Senior  Surgeon  and  Honorary  Medical  Officer  in 
charge  of  the  Electrical  Department,  Eoyal  Devon  Hosp. 
12mo,  Cloth,  88  Pages,  Illustrated $1.00  net. 

HELLMAN:     Amnesia    and    Analgesia    in    Parturition — 

Twilight  Sleep.    By  Alfred  M.  Hellman,  b.a.,  m.d.,  p.a.o.s. 

8vo,  Cloth,  with  Charts,  200  Pages $1.50  net. 

HEW  ATT:     The   Examination    of   the   TJrine,    and    Other 

Clinical  Side  Eoom  Methods.     By  Andrew  Fergus  Hewatt, 

M.B.,   CH.B.,   M.R.C.P.   Edin. 

16mo,  5th  Edition,  Numerous  Illustrations $1.00  net. 

HOFMANN-GAESON :  Eemedial  Gymnastics  for  Heart 
Affections.  Used  at  Bad-Nauheim.  Being  a  Translation 
of  "Die  Gymnastik  der  Herzleidenden  "  von  Dr.  Med.  Julius 
Hofmann  und  Dr.  Med.  Ludwig  Pohlman.  Berlin  and  Bad- 
Nauheim.  By  John  George  Garson,  m.d.  Edin.,  etc.  Physi- 
cian to  the  Sanatoria  and  Bad-Nauheim,  Eversley,  Hants. 
With  51  Full-page  Illustrations  and  Diagrams.  Large  8vo, 
Cloth,  xvi+128  Pages $2.00  net. 

HOWAED:     The  Therapeutic  Value  of  the  Potato.     By 
Heaton  C.  Howard,  l.r.c.p.  Lond.,  m.r.c.s.  Eng. 
8vo,  Paper,   vi-|-31  Pages,   Illustrated 50c 

JELLETT:  A  Short  Practice  of  Midwifery  fob  Nurses. 
Embodying  the  treatment  adopted  in  the  Eotunda  Hospital, 
Dublin.  By  Henry  Jellett,  b.a.,  m.d.  (Dublin  University), 
F.R.C.P.L,  Master  Eotunda  Hospital;  Extern  Examiner  in 
Midwifery  and  Gynecology,  Victoria  University,  Manchester; 
Late  King's  Professor  of  Midwifery;  University  of  Dublin. 
With  Six  Plates  and   169   Illustrations  in   the  Text,  also 


EOEBEB'S  MEDICAL  MONOGBAPHS  7 

an  Appendix,  a  Glossary  of  Medical  Terms,  and  the  Begu- 

lations  of  the  Central  Midwives  Board. 

12mo,  Cloth,  xvi+508  Pages $2.50  net. 

KENWOOD:  Public  Health  Laboratory  Work.  By  Henry 
B.  Kenwood,  m.b.,  f.r.s.  Edin.,  p.p.h.,  f.c.s.,  Chadwick. 
Professor  of  Hygiene  and  Public  Health,  University  of  Lon- 
don; Medical  Officer  of  Health  and  Public  Analyst  for  the 
Metropolitan  Borough  of  Stoke  Newington;  Examiner  in 
Public  Health  to  the  Boyal  College  of  Physicians  and 
Surgeons,  London,  etc. 
6th  Edition,  8vo,  Cloth,  418  Pages,  Illustrated $4.00  net. 

KJEBLEY:     What  Every  Mother  Should  Know  About  Her 
Infants  and  Young  Children.    By  Charles  Gilmore  Kerley, 
m.d.     Professor  of  Diseases  of  Children,  N.  Y.  Polyclinic 
Medical    School    and    Hospital. 
8vo,  Paper,  107  Pages 35c  net. 

KETTLE:  The  Pathology  of  Tumors.  By  E.  H.  Kettle, 
M.D.,  B.S.,  Assistant  Pathologist,  St.  Mary's  Hospital,  and 
Assistant  Lecturer  on  Pathology,  St.  Mary's  Hospital  Med- 
ical School.    About  240  Pages,  126  Illustrations. .  .$3.00  net. 

LEWEES:  A  Practical  Textbook  of  the  Diseases  of 
Women.  By  Arthur  H.  N.  Lewers,  m.d.  Lond.  Senior 
Obstetric  Physician  to  the  London  Hospital;  Late  Examiner 
in  Obstetric  Medicine  at  the  University  of  London;  Univer- 
sity Scholar  &  Gold  Medallist  in  Obstetric  Medicine,  London 
University,  etc. 

With  258  Illustrations,  13  Colored  Plates,  5  Plates  in  Black 
and  White.    7th  Edition,  8vo,  Cloth,  xii-|-540  Pages. $4.00  net. 

LEWIS:  Clinical  Disorders  of  the  Heart  Beat.  A  Hand- 
book for  Practitioners  and  Students.  By  Thomas  Lewis,  m.d., 
d.sc,  f.r.c.p.  Assistant  Physician  and  Lecturer  in  Cardiac 
Pathology,  University  College  Hospital  Medical  School, 
Physician  to  Out-Patients,  City  of  London  Hospital  for 
Diseases  of  the  Chest. 
3rd  Ed.,  8vo,  Cloth,  116  Pages,  54  Illustrations.  .$2.00  net. 

LEWIS:     Lectures  on  the  Heart.     Comprising  the  Herter 
Lectures  (Baltimore),  a  Harvey  Lecture  (New  York),  and 
an  Address  to  the  Faculty  of  Medicine  at  McGill  University 
(Montreal).     By  Thomas  Lewis. 
124  Pages,  with  83  Illustrations $2.00  net. 

LEWIS :  Clinical  Electrocardiography.  By  Thomas  Lewis. 
8vo,  Cloth,  120  Pages,  with  Charts $2.00  net. 

LEWIS :  The  Mechanism  of  the  Heart  Beat.  With  Special 
Eeference  to  Its  Clinical  Pathology.  By  Thomas  Lewis. 
Large  8vo,  Cloth,  295  Pages,  227  Hlus $7.00  net. 


8  EOEBEB'S  MEDICAL  MONOGBAPHS 

McCLUBE:  A  Handbook  of  Fevers.  By  J.  Campbell  Mc- 
Clure,  M.D.,  Glasgow.  Physician  to  Out-Patients,  The 
French  Hospital,  and  Physician  to  the  Margaret  Street 
Hospital  for  Consumption  and  Diseases  of  the  Chest,  London. 
8vo,  Cloth,  470  Pages,  with  Charts $3.50  net. 

McCBUDDEN:    The  Chemistry,  Physiology  and  Pathology 
op  Uric  Acid,  and  the  Physiologically  Important  Purin 
Bodies.    With  a  Discussion  of  the  Metabolism  in  Gout.    By 
Francis   H.   MeCrudden. 
12mo,  Paper,  318  Pages $2.00  net. 

McKISACK:    Systematic   Case  Taking.     A  Practical  Guide 
to  the  Examination  and  Eecording  of  Medical  Cases.     By 
Henry  Lawrence  McKisack,  m.d.,  m.r.c.p.  Lond.     Physician 
to  the  Eoyal  Victoria  Hospital,  Belfast. 
12mo,  Cloth,  166  Pages $1.50  net. 

MACKENZIE:     Symptoms  and  Their  Interpretations.    By 
James  Mackenzie,  m.d.,  ll.d.  Aber.  and  Edin.     Lecturer  on 
Cardiac  Eesearch,   London   Hospital. 
8vo,  Cloth,  Illustrated,  xxii-|-304  Pages $3.00  net. 

MACMICHAEL:  The  Gold-Headed  Cane.  By  William  Mac- 
michael.  Eeprinted  from  the  2nd  Edition.  With  a  Preface 
by  Sir  William  Osier  and  an  Introduction  by  Dr.  Francis  E. 
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EOEBER'S  MEDICAL  MONOGRAPHS  9 

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HOEBEB'S  MEDICAL  MONOGBAPHS  11 

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12  '  EOEBEB'S  MEDICAL  MONOGBAPHS 

WATSON:  Gonorrhoea  and  Its  Complications  in  the  Male 
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Lock  Hospital  Dispensary,  Surgeon  for  Venereal  Diseases, 
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WHITE:     The  Pathology  of  Growth.  Tumours.  By  Charles 
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Eesearch  Fund,  Pathologist  Christie  Hospital,  Special  Lec- 
turer in  Pathology,  University  of  Manchester. 
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WHITE:  Occupational  Affections  of  the  Skin.  A  brief 
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Vice-President,  Senior  Physician  and  Dermatologist,  Eoyal 
Albert  Edward  Infirmary,  Wigan,  Vice-President,  Assoc. 
Certif.  Fact.  Surgeon;  Life  Fellow,  Lond.  Dermat.  Society. 
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WICKHAM  and  DEGEAIS:  Radium.  As  employed  in  the 
treatment  of  Cancer,  Angiomata,  Keloids,  Local  Tuberculosis 
and  other  affections.  By  Louis  Wickham,  M.v.o.  Mfidecin 
de  St.  Lazare;  Ex-Chef  de  Clinique  a  L'Hopital  St. 
Louis,  and  Paul  Degrais,  Ex-Chef  de  Laboratoire  a  L'Hdpital 
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WRENCH :     The  Healthy  Marriage.    A  Medical  and  Psycho- 
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Past  Assistant  Master  of  the  Rotunda  Hospital,  Dublin. 
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WRIGHT:     Tee  Unexpurgated  Case  against  Woman  Suf- 
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WRIGHT:  On  Pharmaco-Thebapy  and  Preventive  Inocu- 
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YOUNG:  The  Mentally  Defective  Child.  By  Meredith 
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Complete  catalogue  and  descriptive  circulars  sent  on  request. 


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